Antibacterial 3-(5-tetrazolyl) penam compounds

ABSTRACT

Certain novel 6-acylamino-2,2-dimethyl-3-(5-tetrazolyl)penam derivatives, and salts thereof; their use as broad-spectrum antibacterial agents; and methods for their preparation. Their preparation comprises acylation of the novel intermediate, 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam or simple derivatives thereof, followed, in some cases, by further transformations of the 6-acylamino group or by removal of a protecting group from the 5-tetrazolyl moiety. Process for the preparation of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, simple derivatives thereof and intermediates therefor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 786,817 filedApr. 12, 1977, now U.S. Pat. No. 4,143,039 of Mar. 6, 1979 which is acontinuation-in-part of application Ser. No. 561,147, filed Mar. 24,1975; which is a continuation-in-part of application Ser. No. 491,510,filed July 24, 1974, and now abandoned; which is a continuation-in-partof application Ser. No. 450,435, filed Mar. 12, 1974, and now abandoned;which in turn is a continuation-in-part of application Ser. No. 407,097,filed Oct. 17, 1973, and now abandoned.

BACKGROUND OF THE INVENTION

2. Field of the Invention

This invention relates to novel antibacterial agents which are of valueas animal feed supplements, as therapeutic agents for the control ofinfectious diseases caused by gram-positive and gram-negative bacteria,and for the sterilization of hospital surfaces and the like; and tonovel intermediates for their production. More specifically, theantibacterial compounds of the instant invention are 6-acyl derivativesof 6-amino-2,2-dimethylpenam, which also bear a 5-tetrazolyl group orcertain 1- or 2-substituted 5-tetrazolyl groups at the 3-position of thepenam nucleus.

2. Description of the Prior Art

In spite of the large number of penam derivatives which have beenproposed for use as antibacterial agents, there still exists a need fornew agents.

U.S. Pat. Nos. 3,427,302 and 3,468,874 disclose penam derivatives whichincorporate a tetrazolyl group as part of the 6-acylamino substituent;however, the compounds of the instant invention are unique in having atetrazolyl group bonded directly to the penam nucleus.

The vast majority of penam compounds disclosed in the prior art have acarboxylic acid group (or a salt thereof) attached to the 3-position.However, penam compounds with other carboxylic acid derivatives at theC-3 locus are also known. Penam-3-carboxylic acid esters have beendisclosed, for example, by Kirchner et al., Journal of OrganicChemistry, 14, 388 (1949); Carpenter, Journal of the American ChemicalSociety, 70, 2964 (1948); Johnson, Journal of the American ChemicalSociety, 75, 3636 (1953); Barnden et al., Journal of the ChemicalSociety (London), 3733 (1953) and Jansen and Russell, Journal of theChemical Society (London), 2127 (1965); and penam-3-carboxamides havebeen reported, for example, by Holysz and Stavely, Journal of theAmerican Chemical Society, 72, 4760 (1950), Huang et al., AntimicrobialAgents and Chemotherapy, 493 (1963) and U.S. Pat. No. 3,641,000. Peronet al. (Journal of Medicinal Chemistry, 7, 483 [1964]) prepared several6-(substituted amino)-2,2-dimethyl-penam-3-caroboxylic acid azides,which were subsequently converted into the corresponding 3-isocyanatesand 3-benzylcarbamates. Peron et al. (loc. cit.) also reported certain3-(hydroxymethyl)penam derivatives. Dehydration of the simple amide ofbenzylpenicillin yields the corresponding nitrile (Khokhlov et al.,Doklady Akad. Sci. Nauk S.S.S.R., 135, 875 [1960]).

SUMMARY OF THE INVENTION

It is an object of the instant invention to provide novel6-acylaminopenam compounds, which are valuable either as newantibacterial agents or as intermediates for the preparation of newantibacterial agents. The said novel penam compounds are those offormulae ##STR1## and the salts thereof;

wherein R¹ is an acyl moiety of an organic carboxylic acid;

R² is selected from the group consisting of hydrogen, trialkylsilylhaving from one to four carbon atoms in each of said alkyl groups,alkanoyloxymethyl having from three to eight carbon atoms,1-(alkanoyloxy)ethyl having from four to nine carbon atoms, 3-phthalidyland a tetrazolylpenam nitrogen protecting group, the nature of which isto be defined hereinafter;

and R³ is selected from the group consisting of hydrogen, trialkylsilylhaving from one to four carbon atoms in each of the said alkyl groups,

alkanoyloxymethyl having from three to eight carbon atoms,1-(alkanoyloxy)ethyl having from four to nine carbon atoms and3-phthalidyl.

The novel penam compounds which are useful an antibacterial agents arethose compounds of formulae I and II wherein R¹ is an acyl group and R²and R³ are each selected from the group consisting of hydrogen, the saidalkanoyloxymethyl, the said 1-(alkanoyloxy)ethyl and 3-phthalidyl.Particularly desirable penam compounds of the present invention, byvirtue of their high activity against a wide range of pathogenicbacteria, are those compounds of formulae I and II, wherein R² and R³are each hydrogen and R¹ is mono- or disubstituted acetyl group, suchas, for example, 2-arylacetyl, 2-amino-2-arylacetyl and 2-(substitutedamino)-2-arylacetyl. The compounds of formulae I and II, wherein R¹ isan acyl group, R² is selected from the group consisting of trialkylsilylhaving from one or four carbon atoms in each of said alkyl groups and atetrazolylpenam nitrogen protecting group, and R³ is trialkylsilylhaving from one to four carbon atoms, are useful as intermediates forthe preparation of the antibacterial agents of this invention.

It is a further object of this invention to provide novel penamcompounds which are useful as intermediates for the preparation of thecompounds of formulae I and II. These novel intermediates are those offormulae: ##STR2## and the salts thereof;

wherein R⁵ is selected from the group consisting of hydrogen,trialkylsilyl having from one to four carbon atoms in each of the saidalkyl groups and an amino protecting group, the nature of which is to bedefined hereinafter

and R² and R³ are as previously defined.

The compounds of formulae III and IV, wherein R², R³ and R⁵ are eachselected from the group consisting of hydrogen and trialkylsilyl havingfrom one to four carbon atoms in each of said alkyl groups areespecially valuable for the preparation of the novel penam compounds offormulae I and II.

In this context, the term "amino protecting group" is intended tocontemplate all protecting groups known, or obvious, to one withordinary skill in the art, which will (a) permit synthesis of a compoundof formula III wherein R⁵ is the said amino protecting group and R² is atetrazolylpenam nitrogen protecting group; and (b) can be removed eitherfrom a compound of formula III, wherein R⁵ is the said amino protectinggroup and R² is a tetrazolylpenum nitrogen protecting group, or from acompound of formula III, wherein R⁵ is the said amino protecting groupand R² is hydrogen, using conditions wherein the penam ring systemremains substantially intact. Thus, when R⁵ is an amino protectinggroup, it can represent any group which will effectively protect the6-amino moiety of 6-aminopenicillanic acid, during the process to bedescribed in detail later in this specification, for the conversion of6-(protected amino)penicillanic acid into the said compounds of formulaIII, and is removable under conditions which do not destroy the β-lactamring system. All such groups are to be considered within the scope ofthis invention, since the importance of the amino protecting groupresides in its ability to perform in the above-described manner.Identification and selection of individual groups which can be used willbe readily accomplished by one skilled in the art, and the nature of thegroup chosen does not affect the novelty of the antibacterial agents ofthis invention in any way. Examples of several groups which can be usedas amino protecting groups for the purposes of this invention areenumerated hereinafter.

In like manner, the term "tetrazolylpenam nitrogen protecting group" isintended to connote all groups known, or obvious, to one skilled in theart, which can be used (a) to permit the synthesis of a compound offormula III, wherein R⁵ is an amino protecting group and R² is the saidtetrazolylpenam nitrogen protecting group, by the process starting with6-(protected amino)penicillanic acid described hereinafter; and (b) canbe removed from a compound of formula I, wherein R¹ is an acyl group andR² is the said tetrazolylpenam nitrogen protecting group, or from acompound of formula III, wherein R⁵ is hydrogen and R² is the saidtetrazolylpenam protecting group, or from a compound of formula III,wherein R⁵ is an amino protecting group and R² is the saidtetrazolylpenam nitrogen protecting group, using conditions wherein thepenam ring system remains substantially intact. The tetrazolylpenamnitrogen protecting group is required in order to protect the nitrogenatom which ultimately becomes N-1 of the tetrazole ring in the saidcompounds of formulae I and III, during the conversion of a 6-(protectedamino)penicillanic acid into a compound of formula III. It is likewisethe ability of the tetrazolylpenam nitrogen protecting group to performa specific function, to be discussed in more detail hereinafter, ratherthan its precise chemical structure, which is important; and the noveltyof the antibacterial agents of the invention does not depend upon thestructure of the protecting group. Selection and identification ofappropriate protecting groups can be made readily and easily by oneskilled in the art, and examples of several applicable groups are givenhereinafter.

A still further object of this invention is to provide a process for theproduction of a compound of formula I and II, which comprises acylatinga compound of formula III or IV, wherein R⁵ is selected from the groupconsisting of hydrogen and trialkylsilyl having from one to four carbonatoms in each of said alkyl groups, and R² and R³ are as previouslydefined.

Yet another object of this invention is to provide a process for theintermediates of formula III, wherein R⁵ is an amino protecting groupand R² is a tetrazolylpenam nitrogen protecting group, which comprisesthe novel sequence of: (a) converting a 6-(protected amino)penicillanicacid into an amide of formula ##STR3## (b) contacting the said amidewith an imidoyl halide forming agent, in the presence of a tertiaryamine; and (c) contacting the so-produced imidoyl halide with a sourceof azide ion; wherein (R⁵)' is an amino protecting group and G is atetrazolylpenam nitrogen protecting group or a group which is readilyconvertible to a tetrazolylpenam nitrogen protecting group during orafter the instant process.

The novel intermediates so produced are used to prepare the penamcompounds of formulae I and II by methods to be discussed in detailhereinafter.

A further additional object of this invention is to provide a method forthe treatment and prevention of infectious diseases caused bygram-positive and gram-negative bacteria; for the topical control ofbacteria on human tissue, hospital surfaces and the like; and for thesupplementation of animal feeds; which comprises utilizing an effectiveamount of compound of formula I or II, or a salt thereof, wherein R¹ isan acyl group and R² and R³ are each selected from the group consistingof hydrogen, alkanoyloxymethyl having from three to eight carbon atoms,1-(alkanoyloxy)ethyl having from four to nine carbon atoms and3-phthalidyl.

Several other aspects of the invention will become apparent from thediscussion which follows.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to certain novel compositions of matter, whichare valuable as antibacterial agents, and as intermediates for thepreparation of antibacterial agents. For the sake of convenience thesecompounds are identified as derivatives of "penam", which has beendefined by Sheehan et al., in the Journal of the American ChemicalSociety, 75, 3293 (1953), as referring to the structure: ##STR4##Although the term penam does not normally carry any stereochemicalimplications, the stereochemistry of the penam compounds of the instantinvention corresponds to that found in the naturally-occurringpenicillins. Using this terminology, the well-known antibioticpenicillin G (benzylpenicillin) is designated as6-(2-phenylacetamido)-2,2-dimethylpenam-3-carboxylic acid.

Many of the compounds of this invention are also 5-substitutedtetrazoles, and 5-substituted tetrazoles can exist in two isomericforms, viz: ##STR5## As will be appreciated by one skilled in the art,when the substituent R² is hydrogen, the two forms co-exist in adynamic, tautomeric, equilibrium mixture. However, in the case where R²is a substituent other than hydrogen, the two forms represent differentchemical entities, which do not spontaneously interconvert.

The new antibacterial agents of this invention are the compounds offormulae I and II, and the salts thereof, wherein R¹ is an acyl moietyof an organic carboxylic acid, and R² and R³ are each selected from thegroup consisting of hydrogen, alkanoyloxymethyl having from three toeight carbon atoms, 1-(alkanoyloxy)ethyl having from four to nine carbonatoms and 3-phthalidyl. The possession of antibacterial properties bythe said compounds of formulae I and II is not predicated upon theselection of the acyl substituent R¹. Indeed, any acyl moiety of anycarboxylic acid can serve as R¹, and all the compounds of formulae I andII, wherein R² and R³ are each selected from the group consisting ofhydrogen, alkanoyloxymethyl having from three to eight carbon atoms,1-(alkanoyloxy)ethyl having from four to nine carbon atoms and3-phthalidyl, which bear an acyl group at R¹, have useful antibacterialproperties. The carboxylic acid from which the acyl group is derived canbe a mono- or polycarboxylic acid. Included within the scope of "acyl"are the acyl moieties of carboxylic acids which themselves cannot beisolated, but which nonetheless exist in the form of their esters,amides, acid chlorides, etc.

However, a particularly favorable configuration of the acyl moiety is:##STR6##

wherein n is 0 or 1;

R⁷ is selected from the group consisting of hydrogen, alkyl having fromone to twelve carbon atoms, alkenyl having from two to twelve carbonatoms, cycloalkyl having from three to seven carbon atoms, cycloalkenylhaving from five to eight carbon atoms, cycloheptatrienyl,1,4-cyclohexadienyl, 1-aminocycloalkyl having from four to seven carbonatoms, cyanomethyl, 5-methyl-3-phenyl-4-isoxazolyl,5-methyl-3-(o-chlorophenyl)-4-isoxazolyl,5-methyl-3-(2,6-dichlorophenyl)-4-isoxazolyl,5-methyl-3-(2-chloro-6-fluorophenyl)-4-isoxazolyl, 2-alkoxy-1-naphthylhaving from one to four carbon atoms in said alkoxy, phenyl, phenoxy,phenylthio, pyridylthio, benzyl, sydnonyl, thienyl, furyl, pyridyl,thiazolyl, isothiazolyl, pyrimidinyl, tetrazolyl, triazolyl, imidazolyl,pyrazolyl, substituted phenyl, substituted phenoxy, substitutedphenylthio, substituted pyridylthio, substituted benzyl, substitutedthienyl, substituted furyl, substituted pyridyl, substituted tetrazolyl,substituted thiazolyl, substituted isothiazolyl, substitutedpyrimidinyl, substituted triazolyl, substituted imidazolyl andsubstituted pyrazolyl, each substituted moiety being substituted by upto two members selected from the group consisting of fluoro, chloro,bromo, hydroxy, hydroxymethyl, amino, N,N-dialkylamino having from oneto four carbon atoms in each of said alkyl groups, alkyl having from oneto four carbon atoms, aminomethyl, aminoethyl, alkoxy having from one tofour carbon atoms, alkylthio having from one to four carbon atoms,2-aminoethoxy and N-alkylamino having from one to four carbon atoms;

and Q is selected from the group consisting of hydrogen, alkyl havingfrom one to six carbon atoms, hydroxy, azido, carboxy, sulfo, carbamoyl,phenoxycarbonyl, indanyloxycarbonyl, sulfoamino, aminomethyl, amino andNH--(CO--CH₂ --NH)_(m) --CO--Z;

wherein Z is selected from the group consisting of alkyl having from oneto six carbon atoms, phenyl, substituted phenyl, furyl, thienyl, pyridylpyrrolyl, amino, N-alkylamino having from one to six carbon atoms,anilino, substituted anilino, guanidino, alkanoylamino having from twoto seven carbon atoms, benzamido, substituted benzamido,thiophenecarboxamido, furancarboxamido, pyridinecarboxamide,aminomethyl, guanidinomethyl, alkanecarboxamidinomethyl having fromthree to eight carbon atoms, benzamidinomethyl, (substitutedbenzamidino)methyl, thiophenecarboxyamidinomethyl,furancarboxamidinomethyl, pyridinecarboxamidinomethyl,pyrrolecarboxamidinomethyl and 2-benzimidazolecarboxamidinomethyl, eachsubstituted moiety being substituted by up to two members selected fromthe group consisting of fluoro, chloro, bromo, iodo, alkyl having fromone to four carbon atoms, alkoxy having from one to four carbon atoms,sulfamyl, carbamoyl and cyano;

and m is 0 or 1;

provided that when R⁷ is 1-aminocycloalkyl, n is 0;

and provided that when R⁷ is selected from the group consisting ofphenoxy, phenylthio, pyridylthio, substituted phenoxy, substitutedphenylthio and substituted pyridylthio and n is 1, Q is selected fromthe group consisting of hydrogen, alkyl having from one to six carbonatoms, carboxy, sulfo, carbamoyl, phenoxycarbonyl, substitutedphenoxycarbonyl, indanyloxycarbonyl and aminomethyl.

Typical examples of the acyl group R¹ are:

2,6-dichlorobenzoyl,

2,6-dimethoxybenzoyl,

2-methoxy-1-naphthoyl,

2-ethoxy-1-naphthoyl,

2-cyanoacetyl,

2-(5-tetrazolyl)acetyl,

5-methyl-3-phenyl-4-isoxazolylcarbonyl,

5-methyl-3-(o-chlorophenyl)-4-isoxazolylcarbonyl,

5-methyl-3-(2,6-dichlorophenyl)-4-isoxazolylcarbonyl,

5-methyl-3-(2-chloro-6-fluorophenyl)-4-isoxazolylcarbonyl,

1-aminocyclobutylcarbonyl,

1-aminocyclopentylcarbonyl,

1-aminocyclohexylcarbonyl,

2-phenylacetyl,

2-(2-thienyl)acetyl,

2-(3-thienyl)acetyl,

2-(2-furyl)acetyl,

2-(3-furyl)acetyl,

2-(4-pyridyl)acetyl,

2-(1-tetrazolyl)acetyl,

2-phenoxyacetyl,

2-(phenylthio)acetyl,

2-(2-pyridylthio)acetyl,

2-amino-2-phenylacetyl,

2-amino-2-(p-hydroxyphenyl)acetyl,

2-amino-2-(p-chlorophenyl)acetyl,

2-amino-2-(m-methoxyphenyl)acetyl,

2-amino-2-(2-thienyl)acetyl,

2-amino-2-(3-thienyl)acetyl,

2-amino-2-(2-furyl)acetyl,

2-amino-2-(3-furyl)acetyl,

2-amino-2-(1,4-cyclohexadienyl)acetyl,

2-hydroxy-2-phenylacetyl,

2-hydroxy-2-(3-thienyl)acetyl,

2-hydroxy-2-(3-furyl)acetyl,

2-hydroxy-2-(1,4-cyclohexadienyl)acetyl,

2-carboxy-2-phenylacetyl,

2-carboxy-2-(3-thienyl)acetyl,

2-carboxy-2-(2-furyl)acetyl,

2-carboxy-2-(1,4-cyclohexadienyl)acetyl,

2-sulfo-2-phenylacetyl,

2-sulfo-2-(2-thienyl)acetyl,

2-sulfo-2-(3-furyl)acetyl,

2-sulfo-2-(1,4-cyclohexadienyl)acetyl,

2-(2-aminoacetamido)-2-phenylacetyl,

2-(4-pyridylthio)acetyl,

2-azido-2-phenylacetyl,

3-amino-2-phenylpropionyl,

2-(m-chlorophenyl)acetyl,

4-methyl-1-(2,6-dichlorophenyl)-5-pyrazolylcarbonyl,

2-(sulfoamino)-2-phenylacetyl,

2-(3-[2-furoyl]ureido)-2-phenylacetyl,

2(3-benzoylureido)-2-phenylacetyl,

2-guanylureido-2-phenylacetyl,

2-guanylureido-2-(3-thienyl)acetyl,

2-(2-guanidinoacetamido)-2-phenylacetyl,

2-(2-guanidinoacetamido)-2-(p-hydroxyphenyl)acetyl,

2-(2-benzamidinoacetamido)-2-phenylacetyl,

2-(2-[3,5-dichlorobenzamidino]acetamido)-2-phenylacetyl,

2-(2-benzamidinoacetamido)-2-(p-hydroxyphenyl)acetyl,

2-(2-[4-pyridinecarboxamidino]acetamido)-2-phenylacetyl,

2-(2-[2-furancarboxamidino]acetamido)-2-(3-thienyl)acetyl and

2-(2-[3-(guanyl)ureido]acetamido)-2-(4-hydroxyphenyl) acetyl.

2-(2-[4-Pyridinecarboxamidino]acetamido)-2-phenylacetyl can also benamed 2-(2-[2-(4-pyridyl)-1-formamidino]acetamido)-2-phenylacetyl, andrefers to the structure: ##STR7##

A preferred group of antibacterial agents of the present inventionconsists of the compounds of formulae I and II, wherein R² and R³ areeach hydrogen and R¹ is of formula V, wherein n is 1 and R⁷ is selectedfrom the group consisting of phenyl, phenoxy, the said substitutedphenyl and the said substituted phenoxy. Within this preferred group,especially valuable subgroups are:

(1) compounds of formulae I and II, wherein R² and R³ are each hydrogenand R¹ is of formula V, wherein n is 1, R⁷ is selected from the groupconsisting of phenyl, phenoxy, said substituted phenyl and saidsubstituted phenoxy and Q is hydrogen;

(2) compounds of formula I and II, wherein R² and R³ are each hydrogenand R¹ is of formula V, wherein n is 1, R⁷ is selected from the groupconsisting of phenyl and said substituted phenyl and Q is amino;

(3) compounds of formulae I and II, wherein R² and R³ are each hydrogenand R¹ is of formulae V, wherein n is 1, R⁷ is selected from the groupconsisting of phenyl and the said substituted phenyl and Q isNH--(CO--CH₂ --NH)_(m) --CO--Z, wherein m is O and Z is selected fromthe group consisting of benzamido, said substituted benzamido,thiophenecarboxamido, furancarboxamido and pyridinecarboxamido;

(4) compounds of formulae I and II, wherein R² and R³ are each hydrogenand R¹ is of formula V, wherein n is 1, R⁷ is selected from the groupconsisting of phenyl and the said substituted phenyl and Q isNH--(CO--CH₂ --NH)_(m) --CO--Z, wherein m is O and Z is aminomethyl;

(5) compounds of formulae I and II, wherein R² and R³ are each hydrogenand R¹ is of formula V, wherein n is 1, R⁷ is selected from the groupconsisting of phenyl and the said substituted phenyl and Q isNH--(CO--CH₂ --NH)_(m) --CO--Z, wherein m is O and Z is selected fromthe group consisting of benzamidinomethyl, said substitutedbenzamidinomethyl, thiophene-carboxamidinomethyl,pyridine-carboxamidinomethyl, 2-benzimidazolecarboxamidinomethyl andpyrrolecarboxamidinomethy; and

(6) compounds of formulae I and II, wherein R² and R³ are each hydrogenand R¹ is of formula V, wherein n is 1, R⁷ is selected from the groupconsisting of phenyl and the said substituted phenyl and Q isNH--(CO--CH₂ --NH)_(m) --CO--Z, wherein Z is guanidino.

A second preferred group of antibacterial agents of this inventionconsists of the compounds of formulae I and II, wherein R² and R³ areeach hydrogen and R¹ is of formula V, wherein n is 1 and R⁷ is selectedfrom the group consisting of sydnonyl, thienyl, furyl, pyridyl,thiazolyl, isothiazolyl, pyrimidinyl, tetrazolyl, triazolyl, imidazolyland pyrazolyl, each of which can be substituted as indicatedhereinbefore. Within this second preferred group, especially valuablesub-groups are:

(1) the said compounds of formulae I and II, wherein Q is hydrogen;

(2) the said compounds of formulae I and II, wherein Q is amino;

(3) the said compounds of formulae I and II, wherein Q is NH--(CO--CH₂--NH)_(m) --CO--Z, wherein m is O and Z is selected from the groupconsisting of benzamido, the said substituted benzamido,thiophenecarboxamido, furancarboxamido and pyridinecarboxamido;

(4) the said compounds of formulae I and II, wherein Q is NH--(CO--CH₂--NH)_(m) --CO--Z, wherein m is O and Z is aminomethyl;

(5) the said compounds of formulae I and II, wherein Q is NH--(CO--CH₂--NH)_(m) --CO--Z, wherein Z is guanidino; and

(6) the said compounds of formulae I and II, wherein Q is NH--(CO--CH₂--NH)_(m) --CO--Z, wherein m is O and Z is selected from the groupconsisting of benzamidinomethyl, said substituted benzamidinomethyl,thiophenecarboxamidinomethyl, pyridinecarboxamidinomethyl,2-benzimidazolecarboxamidinomethyl and pyrrolecarboxamidinomethyl.

When R⁷ is an aromatic carbocyclic group, especially preferred groupsare phenyl and 4-hydroxyphenyl; when R⁷ is a heteroaryl group,particularly preferred groups are thienyl and furyl.

Individual compounds of the instant invention which are extremelyvaluable are:

6-(2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[3-chloro-4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[2-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[3-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-[2-(4-pyridinecarboxamidino)acetamido]-2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-[3-(guanyl)ureido]-2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-[2-(2-pyrrolecarboxamidino)acetamido]-2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-[2-aminoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-[2-aminoacetamido]-2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-[2-aminoacetamido]-2-[2-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-[2-aminoacetamido]-2-[3-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[2-(aminomethyl)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-[2-(4-pyridinecarboxamidino)acetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

6-(D-2-[2-(3-[guanyl]ureido)acetamido]-2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,and

6-(2-[2-(aminomethyl)phenyl]acetamido)-2,2-dimethyl-3-(1-pivaloyloxymethyltetrazol-5-yl)penam.

As will be recognized by one skilled in the art, the acyl group R¹ cancontain one or more asymmetric centers, and asymmetric centers can existin one or two forms, the so-called R- and S-forms. Both forms of eachasymmetric center, and all combinations of each of the forms, are to beconsidered within the scope and purview of this invention. ##STR8##

When contemplating methods to be used for the synthesis of theantibacterial agents of this invention of formulae I and II, wherein R¹is an acyl group R² and R³ are each hydrogen, they can be preparedstarting from the well-known intermediate 6-aminopenicillanic acid(6-APA), and several of the ways in which this can be accomplished areoutlined diagrammatically in Scheme I. Ways in which the antibacterialagents of formulae I and II, wherein R¹ is an acyl group and R² and R³are each selected from the group consisting of alkanoyloxymethyl,1-(alkanoyloxy)ethyl and phthalidyl, are prepared, are outlined inScheme II. However, in Scheme II, for the sake of simplicity, thesubstituent R²⁶ has been shown only at N-1 of the tetrazole ring.However, as explained hereinafter, alkylation of a 5-monosubstitutedtetrazole results in a mixture of monoalkylated products, in which thenewly-introduced group is located at either N-1 or N-2 of the tetrazolering.

From a consideration of Scheme I, the manner in which the compounds offormulae I and III, wherein R² is a tetrazolylpenam nitrogen protectinggroup, are useful as intermediates for antibacterial agents of theinvention will be apparent. When considering the nature of the saidtetrazolylpenam nitrogen protecting group, the group must fulfill twofunctions. First, it must permit the synthesis of compounds of formulaIII, wherein R⁵ is an amino protecting group and R² is the saidtetrazolylpenam nitrogen protecting group. Second it must be removablefrom a compound of formula I, wherein R¹ is an acyl group and R² is thetetrazolylpenam nitrogen protecting group; or from a compound of formulaIII, wherein R⁵ is hydrogen and R² is the tetrazolylpenam nitrogenprotecting group; or from a compound of formula III, wherein R⁵ is anamino protecting group and R² is the tetrazolylpenam protecting group,in each case under conditions wherein the penam ring system remainsintact. As will be apparent from the discussion which follows, not allthe tetrazolylpenam nitrogen protecting groups useful in this inventionneed be removable from each of the said compounds of formulae I and III.In order to be useful in this invention, the tetrazolylpenam nitrogenprotecting group needs to be removable from at least one of thefollowing three types of compounds: (a) compounds of formula I, whereinR¹ is acyl and R² is the said tetrazolylpenam nitrogen protecting group;(b) compounds of formula III, wherein R⁵ is hydrogen and R² is thetetrazolylpenam nitrogen protecting group; or (c) compounds of formulaIII, wherein R⁵ is an amino protecting group and R² is thetetrazolylpenam nitrogen protecting group. The conditions which it willbe necessary to use for removal of a given tetrazolylpenam nitrogenprotecting group will be known, or obvious, to one skilled in the art.Moreover, the reaction conditions which can be used without causingdecomposition of the penam ring system are also well-known, and obvious,by reference to the prior art on penam compounds.

An example of a typical tetrazolylpenam nitrogen protecting group is##STR9## wherein Y is an electron-withdrawing group, and Y' is eitherhydrogen or a further electron-withdrawing group, which can be the sameas or different from Y. The function of the electron-withdrawing groupis to render a hydrogen atom, on the carbon atom to which Y and Y' areattached, sufficiently acidic that the group is removable in aretrograde Michael reaction. Such a reaction is well-known in the art.For example consult House, "Modern Synthetic Reactions," W. A. Benjamin,Inc., New York/Amsterdam, 1965, page 207. Typical electron-withdrawinggroups are cyano, alkoxycarbonyl having from two to seven carbon atoms,phenoxycarbonyl, alkylsulfonyl having from one to six carbon atoms,phenylsulfonyl and SO₂ --NR¹⁵ R¹⁶, wherein R¹⁵ and R¹⁶ are each selectedfrom the group consisting of hydrogen, alkyl having from one to fourcarbon atoms, phenyl and benzyl. A particularly convenient configurationfor this protecting group is that wherein Y' is hydrogen; and preferredvalues for Y are alkoxycarbonyl having from two to seven carbon atomsand phenylsulfonyl.

A further tetrazolylpenam nitrogen protecting group which can be used isa grouping of formula --C(═O)--O--R¹⁴. Such a grouping can be removed bymild hydrolysis, such as mild alkaline hydrolysis, or by treatment witha nucleophile, such as a primary or secondary amine, or a thiolateanion. A wide variety of groups can serve as R¹⁴, but particularlyconvenient groups are alkyl having from one to six carbon atoms, benzyl,phenyl and substituted phenyl, for example, phenyl substituted by up totwo moieties each selected from the group consisting of nitro, fluoro,chloro, bromo, alkyl having from one to four carbon atoms and alkoxyhaving from one to four carbon atoms.

A still further tetrazolylpenam nitrogen protecting group which can beused is a grouping of formula --SO₂ --R¹⁴. Such a group is also removedby hydrolysis, or by treatment with a nucleophilic agent, as indicatedfor the group C(═O)--O--R¹⁴ and convenient values for R¹⁴ are also alkylhaving from one to six carbon atoms, benzyl, phenyl and substitutedphenyl, for example, phenyl substituted by up to two moieties eachselected from the group consisting of nitro, fluoro, chloro, bromo,alkyl having from one to four carbon atoms and alkoxy having from one tofour carbon atoms.

A yet further tetrazolylpenam nitrogen protecting group which can beused is:

    --CH.sub.2 --W

wherein W is phenyl, substituted phenyl, furyl, substituted furyl,thienyl or substituted thienyl. When W is phenyl or substituted phenyl,this group can be removed by hydrogenolysis. This group can also beremoved by solvolysis in trifluoroacetic acid, when the effect of W issufficient to offer the requisite degree of stability to the incipientcarbonium ion:

    CH.sub.2.sup.+ --W

Particularly convenient configurations for this protecting group are:##STR10## wherein R⁴ is at the 3-, 4- or 5-position and it is selectedfrom the group consisting of hydrogen, hydroxy, fluoro, chloro, bromo,iodo, alkyl having from one to six carbon atoms, alkoxy having from oneto six carbon atoms, phenyl and benzyloxy;

R¹⁷ is selected from the group consisting of hydrogen, hydroxy, fluoro,chloro, unbranched-alkyl having from one to six carbon atoms andunbranched-alkoxy having from one to six carbon atoms;

R²⁰ is selected from the group consisting of hydrogen and methyl;

and X is selected from the group consisting of oxygen and sulfur.

As will be recognized by one skilled in the art, other groups which willalso stabilize the carbonium ion (W--CH₂)+ can replace those cited abovefor W.

Still another tetrazolylpenam nitrogen protecting group which can beused is phenacyl or substituted phenacyl. Such a group is removed byreaction with a nucleophilic reagent, such as thiophenoxide. Typicalphenacyl groups which can be used are those of formula ##STR11## whereinR²¹ is selected from the group consisting of hydrogen, nitro, fluoro,chloro, bromo and phenyl.

Several individual methods for the preparation of the antibacterialagents of this invention are now to be discussed and described indetail. For convenience, they will be designated as Methods A, B, C, D,E and F.

Method A is useful for the synthesis of compounds of formulae I and II,wherein R¹ is an acyl group and R² and R³ are each hydrogen. The methodcomprises catalytic hydrogenolysis of a compound of formula I, whereinR¹ is an acyl group and R² is ##STR12## wherein R⁴ and R¹⁷ are aspreviously defined. As will be appreciated by one skilled in the art,conditions must be chosen which do not destroy the β-lactam moiety ofthe penam nucleus. A particularly convenient procedure comprises shakingor stirring a solution of the reactant in a reaction-inert solvent, suchas methanol, ethanol, ethyl acetate or water, or mixtures of thesesolvents, in the presence of a catalyst, such as 10%palladium-on-carbon, under an atmosphere of hydrogen. When hydrogenationis complete, the catalyst is filtered off, and the product is recoveredby solvent evaporation. The catalyst is normally present in an amountfrom about 10% to about 100% by weight based on the penam startingmaterial, and the hydrogen pressure can vary from about one to about onehundred atmospheres. At or around ambient temperature, the reactiontakes a few hours to reach completion.

Method B is useful for preparing compounds of formulae I and II, whereinR¹ is an acyl group, and R² and R³ are each hydrogen. The methodcomprises treating a compound of formula I, wherein R¹ is an acyl group,and R² is ##STR13## wherein R⁴ and R¹⁷ are as previously defined, andwherein at least one of R⁴ and R¹⁷ is a hydroxy group at the 2- or the4-position, with an alkali or alkaline earth metal hydroxide, such assodium, potassium or barium hydroxide. The reaction is carried out bydissolving the starting material in an appropriate solvent, and thenadding at least about one molar equivalent of the hydroxide, at aboutambient temperature or slightly below. The reaction is usually completewithin about one hour, and in some cases the salt of the productcorresponding to the base used precipitates, and it can then be filteredoff. In other cases where the product does not precipitate, it can berecovered by solvent evaporation. If desired, it can then be purified bywell-known methods such as crystallization, solvent extractions orchromatography. Appropriate solvents for this process are those whichwill serve to dissolve the starting material, but will not adverselyinteract with either the starting penam, the product or the particularbase chosen. Examples of solvents which find utility are lower-alkanols,such as methanol or ethanol, and water. It appears that the primaryfunction of the basic agent is to remove the hydrogen from the phenolichydroxy group of the hydroxybenzyl protecting group.

Method C is useful for the preparation of compounds of formulae I andII, wherein R¹ is an acyl group and R² and R³ are each selected from thegroup consisting of hydrogen, alkanoyloxymethyl having from three toeight carbon atoms, 1-(alkanoyloxy)ethyl having from four to nine carbonatoms and 3-phthalidyl. Broadly, this method comprises acylation of acompound of formula III or IV, or a salt thereof, wherein R⁵ is selectedfrom the group consisting of hydrogen and trialkylsilyl having from oneto four carbon atoms in each of said alkyl groups, and R² or R³ isselected from the group consisting of hydrogen, alkanoyloxymethyl,1-(alkanoyloxy)ethyl, phthalidyl and trialkylsilyl having from one tofour carbon atoms in each of said alkyl groups, followed, if necessary,by treatment with a protic solvent. The latter treatment is necessarywhen either R², R³ or R⁵ is trialkylsilyl. The acylation is carried outby contacting the said compound of formula III or IV, or a salt thereof,with an activated derivative of the appropriate carboxylic acid, in anappropriate solvent system. An activated derivative commonly used is anacid halide, such as an acid chloride. In a typical acylation procedure,approximately one molar equivalent of an acid chloride is added to asolution of the said compound of formula III or IV, or a salt thereof,dissolved in a solvent such as a chlorinated hydrocarbon, for example,chloroform or methylene chloride; an ether, for example, tetrahydrofuranor 1,2-dimethoxyethane; an ester, for example, ethyl acetate or butylacetate; a lower aliphatic ketone, for example, acetone or methyl ethylketone; or a tertiary amide, for example, N,N-dimethylformamide orN-methylpyrrolidone; at a temperature in the range from about -40° C. toabout 30° C., and preferably from about - 10° C. to about 10° C.,optionally in the presence of about one molar equivalent of anacid-binder, e.g., triethylamine, pyridine or sodium bicarbonate. Thereaction is complete within a short period, i.e., approximately onehour, and the product is isolated by techniques well known in the art,having full regard for the sensitive nature of the penam moiety of theproduct. For example, the reaction mixture is evaporated to dryness anda water-immiscible organic solvent and water are added. In those caseswhere the product precipitates, it is filtered off. If the product doesnot precipitate, then the pH of the aqueous phase is adjusted to anappropriate value and the phase containing the product is evaporated.The crude product thus obtained can be purified further if desired. WhenR² and R³ are hydrogen, it is convenient to employ a tertiary aminesalt, for example, the triethylamine salt, of the compound of formulaIII or IV. An alternate procedure useful for the acylation of a compoundof formula III or IV, wherein R², R³ and R⁵ are each hydrogen, with acidhalides involves the use of an aqueous solvent system. In thisprocedure, which approximates the Schotten-Baumann procedure, the acidhalide is added to a solution of the starting material in water, or amixture of water and another inert solvent, at, or slightly below,ambient temperature, with the pH of the solvent being maintained withinthe range from about 6.0 to about 9.0 before, during, and after theaddition. At the end of the reaction, the product can often be inducedto precipitate by adjustment of the pH. Alternatively, it can beextracted into a water-immiscible solvent, which is then evaporated todryness.

Another activated derivative of the carboxylic acid with finds use inMethod C is a mixed anhydride. In this case, a carboxylate salt of theappropriate carboxylic acid is treated with about one molar equivalentof a lower-alkyl chloroformate in a reaction-inert, aprotic organicsolvent, at a temperature in the range from about -20° C. to about 20°C. and preferably at about 0° C. Appropriate salts for this process arealkali metal salts, such as sodium and potassium salts, and tertiaryamine salts, such as triethylamine, tributylamine, N-ethylpiperidine,N,N-dimethylaniline, N-methylmorpholine and pyridine salts; andappropriate solvents are, for example chloroform, methylene chloride,acetonitrile, tetrahydrofuran dioxane and N,N-dimethylformamide. Themixed carboxylic-carbonic anhydride thus formed is usually used in situto acrylate the said compound of formula III or IV. This is normallycarried out by mixing solutions of the preformed mixed anhydride and thecompound of formula III or IV. When R² and R³ are hydrogen, it isparticularly convenient to employ a tertiary amine salt, for example thetriethylamine salt, of the compound of formula III or IV. The acylationis normally conducted at a temperature in the range from about -30° C.to about 20° C., and preferably at about -10° C., and it usually takes afew hours to reach completion. In most instances the mixed anhydride andthe compound of formula III or IV are contacted substantially in a 1:1molar ratio. The product is usually isolated by evaporating the reactionmixture to dryness, and then adding a water-immiscible organic solventand water. By careful adjustment of the pH, the product sometimesprecipitates. In other cases the phases are separated, and theproduct-containing phase is evaporated to dryness. The crude product soobtained can be purified further if desired.

Another variation of Method C, comprises conversion of the carboxylicacid to an active ester, followed by treatment with a compound offormula III or IV or a salt thereof. Active esters which can be used inthis regard are, for example, phenyl esters, such as p-nitrophenyl and2,4,5-trichlorophenyl esters, thiol esters, such as thiol phenyl andthiol methyl esters; and N-hydroxy esters, such as N-hydroxysuccinimideand N-hydroxyphthalimide esters. The esters are prepared by methods wellestablished in the art, and the acylation is conveniently conducted bydissolving the active ester and the said compound of formula III or IV,or a salt thereof, in a dipolar aprotic solvent such asN,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone. Thesolution is stored at about ambient temperature for several hours, forexample overnight, and then the product is isolated by standard methods.In some instances the product can be isolated very simply by causing itto precipitate by the addition of a non-solvent, such as diethyl etheror acetone. It is then filtered off, and it can be purified further ifdesired. In many cases the active ester used in this process can bereplaced by the corresponding acid azide.

A still further variation of Method C which is useful for the acylationof compounds of formulae III and IV comprises contacting the saidcompound of formula III or IV with a carboxylic acid in the presence ofcertain agents known in the art for forming peptide bonds. Such agentsinclude carbodiimides, for example, dicyclohexylcarbodiimide and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, alkoxyacetylenes, forexample methoxyacetylene and ethoxyacetylene, andN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. The reaction is carriedout in an appropriate solvent, i.e., one which will serve to dissolvethe reactants, and does not adversely interact with the startingmaterials or the product, for example acetonitrile,N,N-dimethylformamide and N-methylpyrrolidone.

Implicit in the above description of Method C, is the observation thatin a process for the acylation of a compound of formula III or IV,hydrogen substituents located at R², R³ or R⁵ can successfully bereplaced by trialkylsilyl substituents. Said trialkylsilyl substituentsare then removed, and replaced by hydrogen, at the end of the acylation,simply by brief exposure of the product to a protic solvent system, suchas water or a lower-alkanol, for example methanol or ethanol. By virtueof the ready availability of the starting materials, the trimethylsilylgroup is a preferred member. It can be introduced into the startingpenam of formula III or IV by methods well known in the art, such as,for example, using trimethylchlorosilane or N-trimethylsilylacetamide,as discussed by Birkofer and Ritter in Angewandte Chemie (InternationalEdition in English), 4, 417-418 and 426 (1965). Conditions must bechosen, however, which are compatible with the β-lactam group of thepenam nucleus. Also operative in Method C are the silylated derivativesformed by interaction of the said compounds of formulae III and IV withdichlorodi(lower-alkyl)silanes. The silylation step is carried out bymethods known in the art (for example, German Pat. No. 1,933,187). Afterthe acylation reaction, the silyl group is removed by treatment with aprotic solvent, such as water or a lower-alkanol, for example methanolor ethanol.

Additionally, if desired, the tetrazole ring of a compound of formulaIII or IV, wherein R², R³ and R⁵ are each hydrogen, can be protected byvarious other groups, prior to acylation by Method C. The protectinggroup is then removed, after acylation, to liberate the desiredantibacterial agent of formula I or II, wherein R¹ is acyl and R² and R³are each hydrogen. A wide variety of protecting groups can be used forthis purpose, such as, for example, triphenylmethyl, substitutedtriphenylmethyl, alkoxymethyl, benzyloxymethyl, substitutedbenzyloxymethyl, and cyanomethyl. A particularly convenient group,however, is the triphenylmethyl group.

It will be appreciated by one skilled in the art that not all thevariations discussed under Method C are equally effective or convenientin all cases, for the acylation of a compound of formula III or IV. Therelative effectiveness of a particular variation will differ accordingto a number of factors, such as, for example, the precise structure ofthe said compound of formula III or IV, the availability of startingmaterials, the scale of the reaction and, in particular, the structureand reactivity of the acyl group being introduced. In practice, oneskilled in the art will select the most appropriate variation in eachcase, having full regard for the relevant factors. Moreover, in someinstances certain further precautions and modifications become necessaryor desirable, especially in the cases wherein R¹ has the formula V and nis 1. For example, in the case wherein R¹ is of formula V, wherein n is1 and Q is phenoxycarbonyl, substituted phenoxycarbonyl orindanyloxycarbonyl, use can be made of the acylation technique taught inU.S. Pat. No. 3,679,801. Further, in the preparation of the compounds offormulae I and II, wherein R¹ is of formula V, wherein n is 1, Q iscarboxy and R⁷ is selected from the group consisting of phenyl,substituted phenyl, heterocyclyl and substituted heterocyclyl, themono-acid chloride of the 2-substituted malonic acid precursor is aneffective and useful acylating agent in Method C. Preparation and use ofthe said mono-acid chlorides is taught in Belgian Pat. No. 788,928. Inthe case wherein R¹ is of the formula V, wherein n is 1 and Q is orcontains a basic, primary or secondary, amino group, it is necessary toprotect the amino group in the starting carboxylic acid, prior toactivation of the carboxy group of the said acid. After the amino grouphas been protected, the carboxy group is activated, the acylation iscarried out by one of the methods described under Method C, and then theantibacterial penam compound of formula I or II is obtained by removalof the protecting group. A wide variety of protecting groups known inthe art for protecting amino groups during peptide synthesis can be usedfor this purpose. Groups which have been found to be particularlysuitable are the benzyloxycarbonyl group use of which is taught byDoyle, et al. in the Journal of the Chemical Society (London), 1440(1962), and the enamines formed by interaction of the startingamino-acid with a β-dicarbonyl compound, as taught by Dane and Docknerin the Angewandte Chemie (International Edition in English) 3, 439(1964), and in Chemische Berichte der Deutschen Chemischen Gesellschaft,98, 789 (1965). For the use of other protecting groups, consultGreenstein and Winitz, "Chemistry of the Amino Acids," John Wiley &Sons, Inc., New York/London, 1961, pp. 882-922. In certain instanceswhere n is 1 and Q is or contains a basic amino group, a particularlyvaluable acylation procedure comprises use of the acid chloridehydrochloride of the precursor acid. The acid chloride hydrochloridesare prepared, and the acylation is conducted, by the methods describedfor the preparation of 2-amino-2-phenylacetyl chloride hydrochloride andthe subsequent acylation of 6 -aminopenicillanic acid, respectively(U.S. Pat. No. 3,140,282).

Method D is useful for the preparation of compounds of formulae I andII, wherein R¹ is an acyl group and R² and R³ are eachalkanoyloxymethyl, 1-(alkanoyloxy)ethyl or 3-phthalidyl. This Methodcomprises alkylation of the corresponding compound of formula I or II,wherein R¹ is an acyl group and R² and R³ are each hydrogen, with analkanoyloxymethyl, 1-(alkanoyloxy)ethyl or 3-phthalidyl halide. In thiscontext, the term "halide" is intended to contemplate iodide, bromideand chloride. The reaction is conveniently carried out by dissolving atetrazolate salt of the said compound of formula I or II, wherein R² andR³ are each hydrogen, in a suitable, polar, organic solvent, such asN,N-dimethylformamide, and then adding about one molar equivalent of thealkanoyloxymethyl halide. When the reaction has proceeded essentially tocompletion, the product is isolated by standard techniques. It is oftensufficient simply to dilute the reaction medium with an excess of water,and then adjust the pH to an appropriate value. If the productprecipitates, it is extracted into a water-immiscible organic solventand then recovered by solvent evaporation. The value to which the pHmust be adjusted will vary according to the structure of the substituentR¹, but its approximate value will be readily known to one skilled inthe art. Salts of the starting material which are commonly used arealkali metal salts, such as sodium and potassium salts, and tertiaryamine salts, such as triethylamine, N-ethylpiperidine,N,N-dimethylaniline and N-methylmorpholine salts. The reaction isusually run at about ambient temperature, and the length of time neededto reach completion varies according to a variety of factors, such asthe concentration of the reactants and the reactivity of the reagents.Thus, when considering the halo compound, the iodide reacts faster thanthe bromide, which in turn reacts faster than the chloride. In fact, itis customary, when utilizing a chloro compound, to add up to one molarequivalent of an alkali metal iodide. This has the effect of speeding upthe reaction, and it is postulated that this technique brings about ahalogen exchange, thereby generating in situ some of the more reactiveiodo compound. With full regard for the foregoing factors, reactiontimes of several hours, e.g., overnight, are quite commonly used. Asdiscussed earlier, for any given substituent R¹, the compounds offormulae I and II, wherein R² and R³ are each hydrogen, co-exist in anequilibrium mixture, and it is found that the crude product obtainedfrom alkylation of this mixture also comprises a mixture. The mixtureconsists of mono-alkylated products, in which the newly-introducedalkanoyloxymethyl group is located at either the N-1 or N-2 position ofthe tetrazole moiety. The ratio of products varies according to avariety of factors, such as the structure of the penam, the structure ofthe alkylating agent, and the conditions under which the reaction isrun. In some instances one isomer may be produced almost exclusively.Although this mixture of products can be separated by conventionalmeans, for example by chromatography, both isomers have antibacterialproperties, and the mixture of isomers can be used for the furthersynthetic transformations to be described hereinafter, if desired.

The alkanoyloxyalkyl halides are either known compounds, or they areprepared by known procedures (Ulich and Adams, Journal of the AmericalChemical Society, 43, 662 [1921]; Daehne et al., Journal of MedicinalChemistry, 13, 607 [1970]).

Method E is valuable for the preparation of compounds of formulae I andII, wherein R² and R³ are each selected from the group consisting ofhydrogen, alkanoyloxymethyl, 1-(alkanoyloxy)ethyl and 3-phthalidyl, andR¹ is of formula V, wherein R⁷ is as previously defined, n is 1 and Q isselected from the group consisting of carboxy, sulfoamino, carbamoyl,amino and NH--(CO--CH₂ --NH)_(m) --CO--Z. This Method comprises carryingout further transformations on certain of the compounds of formulae Iand II which are prepared by Method C.

Thus, the compounds of formulae I and II, wherein R² and R³ are eachselected from the group consisting of hydrogen, alkanoyloxymethyl,1-(alkanoyloxy)ethyl and 3-phthalidyl, and R¹ is of formula V, whereinR⁷ is as previously defined, n is 1 and Q is carboxy, can be obtainedfrom the corresponding compound of formula I or II, wherein Q isphenoxycarbonyl, substituted phenoxycarbonyl or indanyloxycarbonyl, bymild hydrolysis of the phenoxycarbonyl, substituted phenoxycarbonyl orindanyloxycarbonyl group to liberate a carboxy group. The reaction iscarried out by exposing the starting material to a mildly-alkalineaqueous solvent system until hydrolysis is substantially complete, forexample according to the procedure of U.S. Pat. No. 3,679,801.

The compounds of formulae I and II, wherein R² and R³ are each selectedfrom the group consisting of hydrogen, alkanoyloxymethyl,1-(alkanoyloxy)ethyl and 3-phthalidyl, and R¹ is of formula I, whereinR⁷ is as previously defined, n is 1 and Q is sulfoamino, can be obtainedfrom the corresponding compound of formula I or II, wherein Q is amino,via direct sulfonation. The sulfonation can conveniently be carried outusing the methods described in U.S. Pat. No. 3,381,001.

The compounds of formulae I and II, wherein R² and R³ are each selectedfrom the group consisting of hydrogen, alkanoyloxymethyl,1-(alkanoyloxy)ethyl and 3-phthalidyl, and R¹ is of formula V, whereinR⁷ is as previously defined, n is 1 and Q is carbamoyl, can be obtainedfrom the corresponding compound of formula I or II, wherein Q isphenoxycarbonyl or, preferably, phenoxycarbonyl substituted by one ormore electron-withdrawing groups, by treatment with ammonia.Particularly convenient substituted phenoxycarbonyl groups are nitro-and dinitro-substituted phenoxycarbonyl groups, and the reaction iscarried out using well-known methods (Consult Johnson, Journal of theAmerican Chemical Society, 75, 3636, [1953]).

The compounds of formulae I and II, wherein R² and R³ are each selectedfrom the group consisting of hydrogen, alkanoyloxymethyl,1-(alkanoyloxy)ethyl and 3-phthalidyl, and R¹ is of formula V, whereinR⁷ is as previously defined, n is 1 and Q is NH--(CO--CH₂ --NH)_(m)--CO--Z, wherein m is O and Z is selected from the group consisting ofalkyl having from one to six carbon atoms, phenyl, substituted phenyl,furyl, thienyl, pyridyl and pyrrolyl, are prepared from thecorresponding compound of formula I or II, wherein Q is amino byreaction with an activated derivative of the appropriate carboxylicacid. The techniques for activation of a carboxylic acid, and foracylation, discussed above under Method C can be used in the instantprocess. In many instances, use of the acid chloride of the carboxylicacid is a particularly convenient technique.

The compounds of formulae I and II, wherein R² and R³ are each selectedfrom the group consisting of hydrogen, alkanoyloxymethyl,1-(alkanoyloxy)ethyl or phthalidyl, and R¹ is of formula V, wherein R⁷is as previously defined, n is 1 and Q is NH--(CO--CH₂ --NH)_(m)--CO--Z, wherein m is O and Z is aminomethyl, are prepared from thecorresponding compound of formula I or II, wherein Q is amino, viacoupling with glycine. The coupling procedure comprises the steps of:(1) protecting the amino function of the glycine; (2) activating thecarboxyl group of the N-protected glycine; (3) reacting the so-producedintermediate with the said compound of formula I or II, or a saltthereof; and (4) removing the N-protecting group. Convenient techniquesfor achieving these steps are taught in Belgian Patent No. 681,660. Theproduct from step (4) can then be coupled with a further glycine unit,to preduce the corresponding compounds of formulae I and II, wherein Qis NH--(CO--CH₂ --NH)_(m) --CO--Z, wherein m is 1 and Z is aminomethyl.

The compounds of formulae I and II, wherein R² and R³ are each selectedfrom the group consisting of hydrogen, alkanoyloxymethyl,1-(alkanoyloxy)ethyl and 3-phthalidyl, and R¹ is of formula V, whereinR⁷ is as previously defined, n is 1 and Q is NH--(CO--CH₂ --NH)_(m)--CO--Z, wherein m is O and Z is anilino or substituted anilino, areprepared from the corresponding compound of formula I or II, wherein Qis amino, by reaction with phenyl isocyanate or a substituted phenylisocyanate. The reaction is carried out by contacting substantiallyequimolar proportions of the isocyanate and the penam compound, or asalt thereof (e.g., the triethylamine salt), in a reaction-inert organicsolvent (e.g., N,N-dimethylformamide) at about ambient temperature. Thereaction requires a few hours (e.g., about three hours,) and the productcan be isolated simply by evaporation of the solvent.

The compounds of formulae I and II, wherein R² and R³ are each selectedfrom the group consisting of hydrogen, alkanoyloxymethyl,1-(alkanoyloxy)ethyl and 3-phthalidyl, and R¹ is of formula V, whereinR⁷ is as previously defined, n is 1 and Q is NH--(CO--CH₂ --NH)_(m)--CO--Z, wherein m is O and Z is guanidino, are prepared from thecorresponding compound of formula I or II, wherein Q is amino, viareaction with a guanylcarbamoylating agent. The guanylcarbamoylatingagents obtained by treatment of 4-guanylsemicarbazide either with asource of nitrous acid, or with certain oxidizing agents, areparticularly valuable in this process. Preparation and use of thesecarbamoylating agents are described in U.S. Pat. Nos. 3,579,501 and3,579,514. The term "amidino" is an accepted synonym for guanyl.

The compounds of formulae I and II, wherein R² and R³ are each selectedfrom the group consisting of hydrogen, alkanoyloxymethyl,1-(alkanoyloxy)ethyl and 3-phthalidyl, and R¹ is of formula V, whereinR⁷ is as previously defined, n is 1 and Q is NH--(CO--CH₂ --NH)_(m)--CO--Z, wherein m is O and Z is guanidinomethyl, are prepared from thecorresponding compound of formula I or II, wherein Q is amino viareaction with the acid chloride hydrochloride of guanidinoacetic acid.The reaction is normally carried out by treating a solution of thestarting penam compound, or a salt thereof, in a polar, organic solventsuch as N,N-dimethylformamide or N,N-dimethylacetamide, at about 0° C.,with guanidinoacetyl chloride hydrochloride. The reaction commonly takesabout two hours to reach completion. The reaction mixture is thenfiltered, and the crude product is caused to precipitate by addition ofan excess of a non-solvent, such as acetone, and then filtered off. Asalt of the starting material is used in those cases wherein R² or R³ ishydrogen, and appropriate salts are, for example, alkali metal salts andtertiary amine salts. In order to achieve a good yield of product, it isusually necessary to utilize at least one molar equivalent, andpreferably up to about four molar equivalents, of the acylating agent.

The compounds of formulae I and II, wherein R² and R³ are each selectedfrom the group consisting of hydrogen, alkanoyloxymethyl,1-(alkanoyloxy)ethyl and 3-phthalidyl, and R¹ is of formula V, whereinR⁷ is as previously defined, n is 1 and Q is NH--(CO--CH₂ --NH)_(m)--CO--Z, wherein m is O and Z is selected from the group consisting ofacylamino, benzamido, substituted benzamido, thiophenecarboxamido,furancarboxamido and pyridinecarboxamido, are prepared from thecorresponding compound of formula I or II, wherein Q is amino, byreaction with the appropriate acylisocyanate. The acylisocyanates areprepared, and the reaction is carried out, according to the proceduresdescribed in U.S. Pat. No. 3,479,339.

The compounds of formulae I and II, wherein R² and R³ are each selectedfrom the group consisting of hydrogen, alkanoyloxymethyl,1-(alkanoyloxy)ethyl and 3-phthalidyl, and R¹ is of formula V, whereinR⁷ is as previously defined, n is 1 and Q is NH--(CO--CH₂ --NH)_(m)--CO--Z, wherein m is 1 and Z is selected from the group consisting ofalkyl having from one to six carbon atoms, phenyl, substituted phenyl,furyl, thienyl, pyridyl, pyrrolyl, aminomethyl, anilino, substitutedanilino, guanidino, guanidinomethyl, acylamino, benzamido, substitutedbenzamido, thiophenecarboxamido, furancarboxamido andpyridinecarboxamido, are prepared in a manner analogous to thatdescribed for the corresponding compound wherein m is O, except that thecorresponding compound of formula I or II, wherein Q is NH--CO--CH₂--NH₂ replaces the compound wherein Q is amino.

The compounds of formula I and II, wherein R² and R³ are each selectedfrom the group consisting of hydrogen, alkanoyloxymethyl,1-(alkanoyloxy)ethyl and 3-phthalidyl, and R¹ is of formula V, whereinR⁷ is as previously defined, n is 1 and Q is NH--(CO--CH₂ --NH)_(m)--CO--Z, wherein m is O and Z is selected from the group consisting ofalkanecarboxamidinomethyl having from three to eight carbon atoms,benzamidinomethyl, substituted benzamidinomethyl,thiophenecarboxamidinomethyl, furancarboxamidinomethyl,pyridinecarboxamidinomethyl, pyrrolecarboxamidinomethyl and2-benzimidazolecarboxamidinomethyl are prepared from the correspondingcompound of formula I or II, wherein Q is NH--CO--CH₂ --NH₂ by reactionwith the appropriate imidate ester (e.g. ethyl benzimidate). Thereaction is normally carried out by contacting substantially equimolarquantities of the imidate ester and the penam compound, or a saltthereof (e.g. the triethylamine salt), in a reaction-inert organicsolvent (e.g. chloroform, N,N-dimethylformamide orN,N-dimethylacetamide) at about ambient temperature. The reactionusually takes several hours (e.g. about six hours), and the product isisolated by evaporating the solvent. Alternatively, in some instances,the product can be induced to precipitate by the addition of anon-solvent, such as hexane, ether or acetone. The imidate esters usedin the instant process are either known compounds or they are preparedby known methods. For example, they can be prepared by theacid-catalyzed addition of an alkanol to the appropriate nitrile (thePinner reaction), by reaction of the corresponding carboxamide with atrialkyloxonium fluoborate (e.g. triethyloxonium fluoborate), or, insome cases, by the base-catalyzed addition of an alkanol to a nitrile.The base-catalyzed reaction is particularly convenient when the cyanomoiety is bonded to an electron-withdrawing group (e.g.4-cyanopyridine). Consult Shriner and Neumann, Chemical Reviews, 35,354-358 (1944); Meerwein, Organic Syntheses, Collective Volume V,1080-1082 (1973); Schaefer and Peters, Journal of Organic Chemistry, 26,412 (1961); Belgian Pat. No. 803,094 and references cited.

Method F is valuable for the preparation of compounds of formulae I andII, wherein R¹ is an acyl group and R² and R³ are each hydrogen. TheMethod comprises hydrolysis of the corresponding compound of formula I,wherein R¹ is an acyl group and R² is a group of formula --C(═O)--O--R¹⁴or SO₂ --R¹⁴ wherein R¹⁴ is selected from the group consisting of alkylhaving from one to six carbon atoms, benzyl, phenyl, and phenylsubstituted by up to two moieties selected from the group consisting ofnitro, fluoro, chloro, bromo, alkyl having from one to four carbon atomsand alkoxy having from one to four carbon atoms. The hydrolysis isnormally carried out by contacting the starting material with an aqueousor partially aqueous solvent system, at a temperature normally in therange from about -5° C. to about 30° C., and preferably from about 10°C. to 25° C., at a pH in the range from about 7.5 to 9.5, and usually atabout 8.5, until hydrolysis is substantially complete. The reactionusually takes about 1 hour to reach completion. It is usual, althoughnot essential, to use a co-solvent in this process. Co-solvents whichcan be used are those which are miscible with water, and will serve todissolve the starting penam compound. Typical examples of co-solventswhich can be used are acetone; lower alkanols, such as methanol andethanol; ethylene glycol; mono- and di(lower-alkyl) ethers of ethyleneglycol, such as 2-methoxyethanol and 1,2-dimethoxyethane;tetrahydrofuran; dioxane and acetonitrile. The product is isolated bymethods well-known in the art.

The starting penam compounds used in Method A are prepared by acylationof the appropriate corresponding compound of formula III, or a saltthereof, wherein R⁵ is selected from the group consisting of hydrogenand trialkylsilyl having from one to four carbon atoms in each of saidalkyl groups and R² is ##STR14## wherein R⁴ is at the 3-, 4- or5-position and it is selected from the group consisting of hydrogen,hydroxy, fluoro, chloro, bromo, iodo, alkyl having from one to sixcarbon atoms, alkoxy having from one to six carbon atoms, phenyl andbenzyloxy; and R¹⁷ is selected from the group consisting of hydrogen,hydroxy, fluoro, chloro, unbranched-alkyl having from one to six carbonatoms and unbranched-alkoxy having from one to six carbon atoms.

The acylation comprises treating the said compound of formula III withan activated derivative of the appropriate carboxylic acid. Theactivation of the carboxylic acids, and the acylation, are carried outusing the procedures described hereinbefore under Method C.

The starting penam compounds of formula I, wherein R² is ##STR15##wherein at least one of R⁴ and R¹⁷ is a hydroxy group at the 2- or the4-position, used in Method B, can be prepared by hydrogenolysis of thecorresponding compound wherein any hydroxy group at R⁴ or R¹⁷ isprotected as its benzyl ether. The reaction is carried out by treatingthe starting material with hydrogen gas in the presence of a catalyst,and the procedure discussed above under Method A is conveniently used.As will be appreciated by one skilled in the art, it is oftenunnecessary to isolate the product from the instant hydrogenolysis, andthe product can be used in situ for Method B. Indeed, in some instances,when the hydrogenolysis is performed in the presence of a basic agent,Method B occurs concomitantly with hydrogenolysis. Moreover, undercertain hydrogenolysis conditions, formation of the penam compound offormula I, wherein R² is a hydroxybenzyl group, is immediately followedby in situ hydrogenolytic removal of the hydroxybenzyl group. Thisproduces the corresponding compounds of formula I or II, wherein R² andR³ are each hydrogen.

The starting penam compounds of formulae III and IV, wherein R², R³, andR⁵ are each hydrogen, used in Method C, can be obtained from theappropriate compound of formula III, or an acid addition salt thereof,wherein R⁵ is hydrogen and R² is selected from the group consisting of##STR16## wherein R⁴ is at the 3-, 4- or 5-position and it is selectedfrom the group consisting of hydrogen, hydroxy, fluoro, chloro, bromo,iodo, alkyl having from one to six carbon atoms, alkoxy haivng from oneto six carbon atoms, phenyl and benzyloxy; R¹⁷ is selected from thegroup consisting of hydrogen, hydroxy, fluoro, chloro, unbranched-alkylhaving from one to six carbon atoms and unbranched-alkoxy having fromone to six carbon atoms; R²⁰ is selected from the group consisting ofhydrogen and methyl; and X is selected from the group consisting ofoxygen and sulfur, provided that at least one substituent selected fromthe group consisting of 2-hydroxy, 4-hydroxy, 4-alkoxy having from oneto six carbon atoms, 2-unbranched-alkoxy having from one to six carbonatoms and 4-benzyloxy is present by treatment with trifluoroacetic acid.Although this is not essential, it is usually preferable to add to thereaction an alkoxybenzene, such as anisole, phenetole or veratrole. Thereaction is conveniently carried out by dissolving the starting materialin a small volume of trifluoroacetic acid, containing anisole,maintaining the solution at a temperature in the range from about 20° C.to about 70° C., and preferably at about 30°-40° C., for an appropriatetime period, and then precipitating the product by the addition of anon-solvent. The product can then be recovered by filtration.

Alternatively, particularly when operating on a small scale, it issometimes convenient to arrest the reaction by rapid evaporation of thetrifluoroacetic acid, at or about ambient temperature, in vacuo. Theamount of trifluoroacetic acid used in this process is not critical,provided that enough is present to efficiently dissolve the startingmaterial, and from about ten molar equivalents to about one hundredmolar equivalents based on the penam compound are commonly used. Aboutone molar equivalent of anisole is normally used, but larger amounts,even as large as ten molar equivalents, may be added if desired. Astarting material which operates particularly efficiently in thisprocess is a sulfonate salt, for example, the methanesulfonate orp-toluenesulfonate salt, of the said compound of formula III. The timecourse of the instant reaction varies according to a variety of factors,such as the reaction temperature, the strucutre of the startingmaterial, the concentration of the solution. However, a convenient modeof operation involves monitoring pilot reactions using nuclear magneticresonance spectroscopy, so that the time period which leads to theoptimum conversion to product for a given set of reaction conditions canbe determined. When working at about 35° C., reaction times in the rangefrom about 0.1 to about 1.5 hours are commonly employed.

The starting penam compounds of formula III and IV, wherein R², R³ andR⁵ are each hydrogen, used in Method C, can also be obtained byhydrogenolysis of the appropriate compound of formula III, or anacid-addition salt thereof, wherein R⁵ is hydrogen and R² is ##STR17##wherein R⁴ is at the 3-, 4- or 5-position and it is selected from thegroup consisting of hydrogen, hydroxy, fluoro, chloro, bromo, iodo,alkyl having from one to six carbon atoms, alkoxy having from one to sixcarbon atoms, phenyl and benzyloxy, and R¹⁷ is selected from the groupconsisting of hydrogen, hydroxy, fluoro, chloro, unbranched-alkyl havingfrom one to six carbon atoms and unbranched-alkyl having from one to sixcarbon atoms. The conditions discussed hereinbefore under Method A canbe used for this transformation.

A still further method for obtaining the starting materials of formulaIII and IV, wherein R², R³ and R⁵ are each hydrogen, comprises removalof a triphenylmethyl or substituted triphenylmethyl protecting groupfrom a compound of formula III or IV, wherein R⁵ is triphenylmethyl orsubstituted triphenylmethyl and R² or R³ is hydrogen. Thetriphenylmethyl or substituted triphenylmethyl group is removed bytreatment of the said compound of formula III or IV with acid, and awide variety of acidic reagents and conditions known in the art forremoval of the triphenylmethyl group are operable in this process. Forexample, it is possible to use a sulfonic acid, such as methanesulfonicacid, benzenesulfonic acid or p-toluenesulfonic acid; an anhydroushydrohalic acid, such as hydrogen chloride or hydrogen bromide; or analkanoic acid, such as acetic acid, propionic acid, chloroacetic acid,trifluoroacetic acid and the like. The reaction is normally carried outby dissolving the starting material in an appropriate solvent and addingabout two molar equivalents of the acid reagent, at or about ambienttemperature. Reaction is complete within about one hour, and the productis present in the reaction medium in the form of the acid-addition saltcorresponding to the acidic reagent used. A solvent should be chosenwhich will dissolve the starting penam, and examples of solvents whichfind use are: ethers, such as diethyl ether, tetrahydrofuran, dioxaneand 1,2-dimethoxyethane; chlorinated hydrocarbons, such as chloroform,methylene chloride and 1,2-dichloroethane; lower aliphatic ketones, suchas acetone, methyl ethyl ketone and methyl isobutyl ketone; esters, suchas ethyl acetate and butyl acetate; hydrocarbons, such as hexane,cyclohexane and benzene; and lower alkanols, such as methanol, ethanoland butanol. Although it is common to use about two molar equivalents ofacid in this process, only one molar equivalent is necessary when eitherthe reaction is carried out in the presence of one molar equivalent ofwater, or the acid is introduced as a monohydrate. However, as will berealized by one skilled in the art, the product from this reactionshould not be exposed to an excess of acid for prolonged periods, sincein this case there is a danger of destroying the β-lactam system. Aparticularly convenient mode of operation for this process, is to choosean acid-solvent system such that the starting material is soluble, butthe acid-addition salt generated during the reaction precipitates as itis formed. It can then be recovered by filtration at the end of thereaction. When using the combination of p-toluenesulfonic acid inacetone, the p-toluenesulfonate salt of the product often precipitates.

In like manner, the starting materials of formula III, wherein R⁵ ishydrogen and R² is selected from the group consisting of--C(═O)--O--R¹⁴, --SO₂ --R¹⁴ and (R⁶)', wherein R¹⁴ is selected from thegroup consisting of alkyl having from one to six carbon atoms, benzyl,phenyl and phenyl substituted by up to two moieties selected from thegroup consisting of nitro, fluoro, chloro, bromo, alkyl having from oneto four carbon atoms and alkoxy having from one to four carbon atoms;and (R⁶)' is selected from the group consisting of ##STR18## wherein R⁴is at the 3-, 4- or 5-position and it is selected from the groupconsisting of hydrogen, hydroxy, fluoro, chloro, bromo, iodo, alkylhaving from one to six carbon atoms, alkoxy having from one to sixcarbon atoms, phenyl and benzyloxy; R¹⁷ is selected from the groupconsisting of hydrogen, hydroxy, fluoro, chloro, unbranched-alkyl havingfrom one to six carbon atoms and unbranched-alkoxy having from one tosix carbon atoms; R²⁰ is selected from the group consisting of hydrogenand methyl; and X is selected from the group consisting of oxygen andsulfur, are prepared from the corresponding compound wherein R⁵ istriphenylmethyl, or substituted triphenylmethyl. The triphenylmethyl orsubstituted triphenylmethyl group is removed by treatment with acid,exactly as described hereinbefore.

The starting materials of formulae III and IV, wherein R⁵ istriphenylmethyl or substituted triphenylmethyl, and R² or R³ ishydrogen, are prepared by a retrograde Michael reaction, on acorresponding compound of formula III, wherein R² is CH₂ CH₂ --Y,wherein Y is selected from the group consisting of cyano, alkoxycarbonylhaving from two to seven carbon atoms, phenoxycarbonyl, alkylsulfonylhaving from one to four carbon atoms, phenylsulfonyl and --SO₂ --NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are each selected from the group consisting ofhydrogen, alkyl having from one to four carbon atoms, phenyl and benzyl.The retrograde Michael reaction comprises treating the said compoundwith about one equivalent of base, using conditions known in the art forretrograde Michael reactions, but which are compatible with the penamring system. Typically, the said compound of formula IV is treated withabout one equivalent of a relatively non-nucleophilic base, in anon-hydroxylic solvent, at a temperature in the range from about 0° C.to about 25° C., for a period of from about ten minutes to about twohours, (Consult further Journal of the Chemical Society [London], PartB, 5867 [1970]).

Preparation of those starting materials for Method C which are compoundsof formulae III and IV, wherein R⁵ is hydrogen, R² and R³ are eachselected from the group consisting of alkanoyloxymethyl having fromthree to eight carbon atoms, 1-(alkanoyloxy)ethyl having from four tonine carbon atoms and 3-phthalidyl, is achieved by alkylation of atetrazolate salt, such as the triethylamine salt of the correspondingcompound of formula III or IV, wherein R² and R³ are hydrogen, using theappropriate alkanoyloxyalkyl or phthalidyl halide. The procedure ofMethod D is used in this process, except that it is common to utilize atleast two molar equivalents, and preferably about three molarequivalents, of the alkylating agent.

Thus, valuable starting materials for production of the antibacterialcompounds of this invention are the novel penam compounds of formulaIII, wherein R² is a tetrazolylpenam nitrogen protecting group and R⁵ isan amino protecting group. These compounds can be prepared by a novelthree-step sequence of reactions, which forms an important embodiment ofthis invention, and which is now to be described in detail for thespecific case wherein R⁵ is triphenylmethyl and R² is selected from thegroup consisting of CH₂ CH₂ V, C(═O)--O--R¹⁴ and (R⁶)', wherein Y, R¹⁴and (R⁶)' are as previously defined.

The said novel penam derivatives of formula III are prepared startingfrom the well-known intermediate, 6-triphenylmethylaminopenicillanicacid, via certain transformations of the C-3 carboxy function.Preparation of 6-triphenylmethylaminopenicillanic acid is taught bySheehan and Henery-Logan in the Journal of the American ChemicalSociety, 81, 5838 (1959).

In Step 1, 6-(triphenylmethylamino)penicillanic acid is converted intoan amide of formula VI, ##STR19## wherein G is selected from the groupconsisting of --C(═O)--O--R¹⁴, --SO₂ --R¹⁴, CH₂ CH₂ Y and (R⁶)'; whereinY and R¹⁴ are as previously defined and (R⁶)' is selected from the groupconsisting of ##STR20## wherein R⁴, R¹⁷, R²⁰ and X are as previouslydefined.

In the case wherein G is --CH₂ CH₂ Y or (R⁶)', the amide of formula VIis prepared by activation of the 3-carboxy group of6-(triphenylmethylamino)penicillanic acid, e.g. by the mixed anhydrideformation, followed by reaction with an amine of formula NH₂ CH₂ CH₂ Yor (R⁶)'--NH₂. Thus, formation of the mixed anhydride involvessuspending or dissolving an appropriate carboxylate salt of the6-triphenylmethylamino-penicillanic acid in a reaction-inert organicsolvent, and then adding to this suspension or solution a reagentselected from pivaloyl chloride and lower-alkyl chloroformates.Appropriate salts are, for example, alkali metal salts, such as sodiumor potassium salts, and amine salts, such as triethylammonium,pyridinium, N-ethylpiperidinium or N,N-dimethylanilinium salts.Appropriate solvents are those which serve to dissolve at least one ofthe reactants, and the mixed anhydride product, and do not adverselyinteract with the reactants or product. Examples of such solvents arechlorinated hydrocarbons, such as chloroform, methylene chloride;aromatic hydrocarbons, such as benzene, toluene and xylene; and ethers,such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. Thereaction is usually carried out at a temperature in the range from about-50° C. to about 30° C., and preferably at about 0° C. At about 0° C.,the reaction commonly requires about one hour. The6-triphenylmethylaminopenicillanic acid salt and the pivaloyl chlorideor lower-alkyl chloroformate are normally present in roughly equimolarproportions, although in some instances a small excess of the acidchloride component is used. The product can be isolated simply byfiltering off the insoluble materials, and then evaporating the solventin vacuo to give the crude product. The latter can be used directly, orpurified further by methods known in the art. If desired, however, themixed anhydride product need not be isolated. It can be used in situ forreaction with the amine of formula NH₂ CH₂ CH₂ Y or (R⁶)'--NH₂. Reactionof the mixed anhydride with the amine of the formula (R⁶)'--NH₂ or NH₂CH₂ CH₂ Y is usually carried out simply by contacting the reactants inan inert solvent, for about 0.5 to about 2.0 hours, at a temperature inthe range from about -30° C. to about 30° C. and preferably at around 0°C. The same solvents identified above for mixed anhydride formation areuseful for the instant reaction, and the reagents are usually used inapproximately equimolar proportions. As will be realized by one skilledin the art, the product should not be exposed to an excess of thestarting amine, since this runs the risk of causing extensivedecomposition of the penam β-lactam. In the cases wherein this reactionis conducted in a water-immiscible solvent, the product is usuallyisolated by washing the reaction mixture with water and thenconcentrating the organic solvent to dryness in vacuo, to give the crudeproduct. The latter product can be used immediately for Step 2, or, ifdesired, it can be purified further by well-known methods. However, itis sometimes convenient simply to wash the reaction mixture with water,and then use the so-produced solution of amide directly in Step 2. Inthe cases wherein the reaction is conducted in a water-miscible solvent,the product is usually isolated by first removing the water-misciblesolvent by evaporation in vacuo, replacing it by a water-immisciblesolvent, and then proceeding as described above.

When the amine (R⁶)'--NH₂ is of formula ##STR21## wherein either R⁴ orR¹⁷ is a hydroxy group, it is convenient to protect the phenolic hydroxygroup of the hydroxybenzylamide produced, before proceeding to Step 2. Awide variety of protecting groups known in the art for protectinghydroxy groups are operative for this purpose. For example, the hydroxygroup can be protected as an alkoxymethyl or tetrahydropyranyl ether, orit can be silylated. The types of silyl derivatives, and the methods ofpreparation, referred to hereinbefore under "Method C" are useful in theinstant process.

In the case wherein g is --C(═O)--O--R¹⁴ or --SO₂ --R¹⁴, the amide offormula VI is prepared by reaction of6-(triphenylmethylamino)penicillanic acid with the appropriateisocyanate of formula R¹⁴ --O--C(═O)--N═C═O or R¹⁴ --SO₂ --N═C═O. Thereaction is usually carried out by contacting substantially equimolarquantities of the reactants, in a reaction inert organic solvent, at atemperature in the range from about 0° C. to about 30° C., for a periodof from about one hour to about twenty hours. The product can beisolated simply by removal of the solvent in vacuo or the solution ofthe amide of formula VI can be used in situ for Step 2. The isocyanatesof formula R¹⁴ --O--(C═O)--N═C═O are prepared by reaction of a carbamateof formula R¹⁴ --O--C(═O)--NH₂ with oxalyl chloride, and the isocyanatesof formula R¹⁴ --SO₂ --N═C═O are prepared by reaction of a sulfonamideof formula R¹⁴ --SO₂ --NH₂ with oxalyl chloride. [See J. Hetero. Chem.,6, 261 (1969).]

In Step 2 of the said novel three-step series of reactions, the productfrom Step 1 is converted into an imidoyl chloride of formula ##STR22##where G is selected from the group consisting of --CH₂ CH₂ --Y,--C(═O)--O--R¹⁴, --SO₂ R¹⁴ and (R⁶)', wherein Y, R¹⁴ and (R⁶)' are aspreviously defined. For imidoyl chloride formation, a convenient methodcomprises dissolving the said amide in a reaction-inert organic solventand then treating the solution with phosgene and a tertiary amine. Aboutone molar equivalent of phosgene is usually used, but amounts up toabout two or three molar equivalents are sometimes employed. Thetertiary amine is preferalby present in a molar amount equal to orgreater than the amount of phosgene. The reaction is carried out at atemperature in the range from about -20° C. to about 30° C., andpreferably at about 25° C., and it usually requires a few hours to reachcompletion. It is sometimes advantageous from a standpoint of hasteningcomplete conversion to imino chloride, to add further quantities oftertiary maine and phosgene as the reaction proceeds. A variety oftertiary amines can be used in this process, for example trimethylamine,triethylamine, N,N-dimethylaniline, N-methylmorpholine and pyridine, andthe like, and typical solvents which can be used are chlorinatedhydrocarbons, such as chloroform, methylene chloride and1,2-dichloroethane, and ethers such as tetrahydrofuran and1,2-dimethoxyethane. If desired, the imidoyl chloride can be isolated byevaporation of the filtered reaction mixture, but in many instances itis convenient to use the imino chloride in situ.

Several other reagents, for example, thionyl chloride or a phosphoroushalide such as phosphorus pentachloride are operative in the imidoylchloride forming reaction. Moreover, if desired, use can be made of thecorresponding imidoyl bromide.

In Step 3 of the said novel three-step series of reactions, the aboveimidoyl chloride is converted into a tetrazolylpenam compound of formula##STR23## wherein G is as previously defined. This transformationcomprises treating the said imidoyl chloride with a source of azide ionand a convenient way of carrying out this transformation involvesdissolving the imidoyl halide in an appropriate solvent, and then addingabout one molar equivalent, or sometimes a small excess, of the azideion source. The reaction mixture is then stored at or about ambienttemperatures for several hours, for example, overnight, until conversioninto tetrazole is substantially complete. A wide variety of azide ionsources are operative in this process, and examples of those which areparticularly valuable are trialkylsilyl azides having from one to fourcarbon atoms in each of said alkyl groups, such as trimethylsilyl azideand triethylsilyl azide; salts of hydrazoic acid, such as potassiumazide and sodium azide, tributylammonium azide, N,N-dimethylaniliniumazide, N-methylmorpholinium azide and pyridinium azide;tetramethylguanidinium azide. Appropriate solvents are those which willserve to dissolve both the imidoyl halide and the azide ion source, butdo not adversely react with either the reactants or the products of theprocess. In the cases where the azide ion source is a trialkylsilylazide or a trisubstituted ammonium azide, chlorinated hydrocarbonsolvents, such as chloroform, methylene chloride and 1,2-dichloroethane,are commonly used. However, dipolar aprotic solvents such asN-methylpyrrolidone, can also be used; and in the cases where a metalsalt of hydrazoic acid constitutes the azide ion source, these dipolaraprotic solvents become the solvent-type of choice. As regards ease ofoperation, and availability of reagents, the use of trimethylsilyl azidein chloroform is particularly convenient. As indicated earlier, thereaction takes several hours to reach completion. However, theconversion to tetrazole can often be hastened by adding furtherquantities of azide ion during the course of the reaction. Productisolation is achieved using standard methods. When a low boilingchlorinated hydrocarbon is the solvent, the reaction solution is washedwith dilute alkali and then the organic solvent is evaporated off. Whena dipolar aprotic solvent is the solvent, the reaction mixture isusually first diluted with a large excess of dilute alkali, and then,after appropriate adjustment of the pH, the product is isolated bysolvent extraction.

As indicated hereinbefore, synthesis of the antibacterial agents of thisinvention involves the use of two kinds of protecting groups, and thesegroups have been identified in terms of their ability to function in aparticular fashion.

The tetrazolylpenam nitrogen protecting group has been identified interms of its ability to fulfill two functions. The first of these, itscapacity to be removed under certain specified conditions, has alreadybeen discussed. The second of these is its ability to permit thesynthesis of a compound of formula III, wherein R⁵ is an aminoprotecting group and R² is the said tetrazolylpenam nitrogen protectinggroup.

From the foregoing discussion it will be apparent that thetetrazolylpenam nitrogen protecting group must be a group which willpermit operation of the above-described three-step series of reactions.That is, it must be of such a nature that the amide of formula VI can beprepared, that the amide can be converted to an imidoyl halide, and thatthe imidoyl halide can be converted to the said 1-protected5-tetrazolylpenam compound of formula III, substantially as described.

In like manner, the amino protecting group must fulfill two functions.The first of these is that, after attachment to the 6-amino function of6-aminopenicillanic acid, it must permit operation of theabove-described three-step series of reactions. That is, it must protectthe penam ring system during formation of the amide of formula VI,during conversion into an imidoyl halide, and during conversion into the1-protected 5-tetrazolylpenam compounds of formula III. The secondfunction of an amino protecting group for use in this invention is thatit must be removable, under conditions which do not decompose the penamring system, from either: (a) a compound of formula III, wherein R⁵ isthe said amino protecting group and R² is a tetrazolylpenam nitrogenprotecting group; (b) a compound of formula III or IV, wherein R⁵ is thesaid amino protecting group and R² or R³ is hydrogen; or (c) a compoundof formula III wherein R⁵ is the said amino protecting group, and R² isselected from the group consisting of alkanoyloxymethyl,1-(alkanoyloxy)ethyl and 3-phthalidyl. Selection of appropriate aminoprotecting groups will be achieved readily and easily by one skilled inthe art. In particular all such groups known in the art for peptidesynthesis and which fit the above criteria are operative. However,particularly convenient protecting groups are triphenylmethyl,substituted triphenylmethyl and β,β,β-trihaloethoxycarbonyl groups, suchas β,β,β-tribromoethoxycarbonyl and β,β,β-trichloroethoxycarbonyl.Examples of substituted triphenylmethyl groups which are especiallyvaluable are those of formula ##STR24## wherein R²², R²³ and R²⁴ areeach selected from the group consisting of hydrogen, fluoro, chloro,bromo, alkyl having from one to four carbon atoms, alkoxy having fromone to four carbon atoms and phenyl. Because of its readilyavailability, the triphenylmethyl group is especially valuable.

The amines of formulae NH₂ CH₂ CH₂ Y and NH₂ --(R⁶)', used in Step 1above, are either known compounds or they are prepared by known methodsfrom commercially-available starting materials. For example, amines offormula ##STR25## can conveniently be prepared from the correspondingaldehyde of formula ##STR26## via conversion to the oxime followed byreduction, or in cases where the R⁴ and/or R¹⁷ groups would beunaffected, by the reductive alkylation of ammonia. (Consult Harrisonand Harrison, "Compendium of Organic Synthetic Methods,"Wiley-Interscience, 1971, pages 233-235 and 258-261).

A further sub-class of novel 3-(5-tetrazolyl)penam compounds which arevaluable antibacterial agents, and which fall within the scope andpurview of the instant invention is those compounds of formulae:##STR27## wherein R⁸ is selected from the group consisting of phenyl,1,4-cyclohexadienyl, 3-sydnonyl, thienyl, furyl, pyridyl, thiazolyl,isothiazolyl, tetrazolyl, triazolyl, imidazolyl, pyrazolyl, substitutedphenyl, substituted thienyl, substituted furyl, substituted pyridyl,substituted thiazolyl, substituted isothiazolyl, substituted triazolyl,substituted imidazolyl and substituted pyrazolyl, each substitutedmoiety being substituted by up to two members selected from the groupconsisting of fluoro, chloro, bromo, hydroxy, alkyl having from one tosix carbon atoms, alkoxy having from one to six carbon atoms, amino andalkylthio having from one to six carbon atoms; R⁹ and R¹⁰ are eachselected from the group consisting of hydrogen, methyl and ethyl; andR¹¹ is selected from the group consisting of hydrogen, alkanoyloxymethylhaving from three to eight carbon atoms, 1-(alkanoyloxy)ethyl havingfrom four to nine carbon atoms and phthalidyl. The compounds of formulaVIII and IX are prepared from the corresponding compound of formula I orII, wherein R¹ is of formula V wherein n is 1, Q is amino and R⁷ is asdefined above for R⁸, and R² and R³ are as defined above for R¹¹, bycondensation of the said compound of formula I and II with theappropriate aldehyde or ketone of formula R⁹ --CO--R¹⁰. The condensationreaction is usually carried out by contacting the starting penamcompound with a large excess of the aldehyde or ketone in the presenceof at least one molar equivalent of a tertiary amine, at or slightlybelow room temperature. A sufficient amount of the aldehyde or ketone isnormally used so that a further solvent is not necessary. However, afurther diluent which does not adversely react with either the startingmaterials or the product can be used if desired. Examples of tertiaryamines which are operative in the process are triethylamine,tributylamine, pyridine, N,N-dimethylaniline, N-methylmorpholine andquinoline. Although at least one equivalent of tertiary amine isrequired, it is common to use a fairly large excess, up to about tenmolar equivalents. The instant process normally requires a reaction timeof several hours, for example overnight. In those cases wherein theproduct is out of solution at the end of the reaction it is filteredoff. Alternatively, when the product is in solution at the end of thereaction, it is recovered by evaporation of the solvent in vacuo.

A still further sub-class of novel 3-(5-tetrazolyl)penam compounds whichare valuable antibacterial agents, and which fall within the scope andpurview of this invention, is those compounds of formulae: ##STR28##wherein R¹² and R¹³ are each alkyl having from one to six carbon atoms,or, when taken together with the nitrogen to which they are attached,they represent a member selected from the group consisting ofpyrrolidino, morpholino, piperidino and azacycloheptan-1-yl; and R¹¹ isas defined above. The compounds of formula X and XI, are prepared fromthe appropriate corresponding compound of formula III or IV, wherein R²and R³ are as defined above for R¹¹ and R⁵ is hydrogen, by introducingthe formamidine moiety, using the methods taught by Lund and Tybring(Nature, New Biology, 236, 135 [1972]).

A characteristic feature of the compounds of formulae I, II, III, IV,VIII, IX, X and XI, wherein R², R³ or R¹¹ are hydrogen, is their abilityto form salts. By virtue of the acidic nature of a 5-monosubstitutedtetrazole, the said compounds have the ability to form salts with basicagents, and these salts, referred to generically as "tetrazolate" saltsin this specification, are to be considered within the scope of thisinvention. The salts can be prepared by standard techniques, such ascontacting the acidic and basic components, usually in a 1:1 molarratio, in an aqueous, non-aqueous or partially aqueous medium, asappropriate. They are then recovered by filtration, by precipitationwith a non-solvent followed by filtration, by evaporation of thesolvent, or, in the case of aqueous solutions, by lyophilization, asappropriate. Basic agents which are suitably employed in salt formationbelong to both the organic and inorganic types, and they includeammonia, organic amines, alkali metal hydroxides, carbonates,bicarbonates, hydrides and alkoxides, as well as alkaline earth metalhydroxides, carbonates, hydrides and alkoxides. Representative examplesof such bases are primary amines, such as n-propylamine, n-butylamine,aniline, cyclohexylamine, benzylamine, p-toluidine and octylamine;secondary amines, such as diethylamine, N-methylaniline, morpholine,pyrrolidine and piperidine; tertiary amines, such as triethylamine,N,N-dimethylaniline, N-ethylpiperidine, N-methylmorpholine and1,5-diazabicyclo[4.3.0]non-5-ene; hydroxides, such as sodium hydroxide,potassium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides,such as sodium ethoxide and potassium ethoxide; hydrides, such ascalcium hydride and sodium hydride; carbonates, such as potassiumcarbonate and sodium carbonate; and bicarbonates, such as sodiumbicarbonate and potassium bicarbonate.

Further, the compounds of formulae I and II, wherein R¹ contains one ormore acidic functions (e.g. carboxy, sulfo etc.), have the ability toform other salts (e.g., salts of the carboxylate and sulfonate type).These salts, which can be prepared in exactly the same manner and usingthe same basic agents, as described above for the tetrazolate salts, arealso within the purview of this invention. Clearly, certain of thecompounds of formulae I and II can form both mono- and poly-salts. Whenconsidering poly-salts, the various cationic moieties can be the same ordifferent.

The compounds of formulae I, II, III and IV which contain a basic group,have the ability to form acid-addition salts. Said acid-addition saltsare also to be considered as being within the scope of this invention.Examples of acid-addition salts which are particularly valuable are:hydrochloride, hydrobromide, phosphate, perchlorate, citrate, tartrate,pamoate, glutarate, benzoate, sulfate, lactate, and arylsulfonate salts.

When therapeutic use in mammals is being contemplated for a salt of acompound of the instant invention, it is of course essential to use apharmaceutically-acceptable salt. However, other salts are useful for avariety of other purposes; such as, for example, isolating and purifyingindividual compounds, changing the solubility characteristics of anindividual compound, and for interconverting pharmaceutically-acceptablesalts with their non-salt counterparts.

The antibacterial penam compounds of the instant invention show activityagainst a wide variety of gram-positive and gram-negative bacteria. Thein vitro activity can be demonstrated by the conventional two-foldserial dilution technique in Brain-Heart Infusion broth (Difco). Thebroth is inoculated with the bacterial culture, and with the testantibiotic, and then it is incubated overnight. On the next day, thetest is read visually. The minimum inhibitory concentration (MIC) is thelowest concentration of antibiotic which prevents turbidity, i.e. whichprevents growth of the microorganism. In vitro activities of several ofthe penam compounds of the invention are presented later in thisspecification.

The in vitro activity of the antibacterial compounds of the instantinvention makes them particularly suitable for topical application, forexample, in the form of creams and ointments, and for the sterilizationof sickroom and hospital surfaces, equipment, and the like.

The antibacterial penam compounds of the instant invention are alsoactive in vivo. In determining such activity, the test antibiotic isadministered to infected mice, using a multiple dosing regimen. Theseverity of the infection varies from about one to about ten times thatneeded to kill 100% of the mice under the conditions of the test. At theend of the test, the activity of a compound is assessed by counting thenumber of survivors among the treated animals. Both the subcutaneous(SC) and the oral (PO) dosage routes are used. Results are given inTable I for two of the compounds of the invention. The ability of thecompounds to protect mice against systemic infections caused by a lethalintraperitoneal inoculum of Staphylococcus aureus or of Escherichia coliis presented.

                  TABLE I                                                         ______________________________________                                                                  Percentage                                                   Dosage           Protection                                          Compound   (mg./kg.) Dosage   S. aureus                                                                             E. coli                                 ______________________________________                                        6-(D-2-amino-                                                                            50        SC       40      20                                      2-[3-thienyl]-                                                                acetamido)-2,2-                                                               dimethyl-3-(5-                                                                tetrazolyl)-                                                                  penam                                                                         6-(D-2-amino-                                                                            25        SC       60      20                                      2-[3-thienyl]-                                                                acetamido)-2,2-                                                               dimethyl-3-(5-                                                                tetrazolyl)-                                                                  penam                                                                         6-(D-2-amino-                                                                            12        SC       50                                              2-[3-thienyl]-                                                                acetamido)-2,2-                                                               dimethyl-3-(5-                                                                tetrazolyl)-                                                                  penam                                                                         6-(D-2-amino-                                                                            6         SC       50                                              2-[3-thienyl]-                                                                acetamido)-2,2-                                                               dimethyl-3-(5-                                                                tetrazolyl)-                                                                  penam                                                                         6-(D-2-amino-                                                                            200       PO               0                                       2-[3-thienyl]-                                                                acetamido)-2,2-                                                               dimethyl-3-(5-                                                                tetrazolyl)-                                                                  penam                                                                         6-(D-2-amino-                                                                            50        SC       80      100                                     2-[p-hydroxy-                                                                 phenyl]acet-                                                                  amido)-2,2-di-                                                                methyl-3-(5-                                                                  tetrazolyl)-                                                                  penam                                                                         6-(D-2-amino-                                                                            25        SC       70      80                                      2-[p-hydroxy-                                                                 phenyl]acet-                                                                  amido)-2,2-di-                                                                methyl-3-(5-                                                                  tetrazolyl)-                                                                  penam                                                                         6-(D-2-amino-                                                                            12        SC       50                                              2-[p-hydroxy-                                                                 phenyl]acet-                                                                  amido)-2,2-di-                                                                methyl-3-(5-                                                                  tetrazolyl)-                                                                  penam                                                                         6-(D-2-amino-                                                                            6         SC       50                                              2-[p-hydroxy-                                                                 phenyl]acet-                                                                  amido)-2,2-di-                                                                methyl-3-(5-                                                                  tetrazolyl)-                                                                  penam                                                                         6-(D-2-amino-                                                                            200       PO               100                                     2-[p-hydroxy-                                                                 phenyl]acet-                                                                  amido)-2,2-di-                                                                methyl-3-(5-                                                                  tetrazolyl)-                                                                  penam                                                                         ______________________________________                                    

The in vivo activity of the antibacterial compounds of this inventionmakes them suitable for the control of bacterial infections in mammals,including man, by both the oral and parenteral modes of administration.The compounds will find wide use in the control of infections caused bysusceptible gram-positive and gram-negative bacteria in human subjects.

When considering therapeutic use of a compound of this invention, or asalt thereof, in a mammal, particularly man, the compound can beadministered alone, or it can be mixed with other antibiotic substancesand/or pharmaceutically-acceptable carriers or diluents. Said carrier ordiluent is chosen on the basis of the intended mode of administration.For example, when considering the oral mode of administration, anantibacterial penam compound of this invention can be used in the formof tablets, capsules, lozenges, troches, powders, syrups, elixirs,aqueous solutions and suspensions, and the like, in accordance withstandard pharmaceutical practice. The proportional ratio of activeingredient to carrier will naturally depend on the chemical nature,solubility and stability of the active ingredient, as well as the dosagecontemplated. In the case of tablets of oral use, carriers which arecommonly used include lactose, sodium citrate and salts of phosphoricacid. Various disintegrants such as starch, and lubricating agents, suchas magnesium stearate, sodium lauryl sulfate and talc, are commonly usedin tablets. For oral administration in capsule form, useful diluents arelactose and high molecular weight polyethylene glycols. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring agents can be added. For parenteral administration,which includes intramuscular, intraperitoneal, subcutaneous andintravenous use, sterile solutions of the active ingredient are usuallyprepared, and the pH of the solutions are suitably adjusted andbuffered. For intravenous use, the total concentration of solutes shouldbe controlled to render the preparation isotonic.

As indicated earlier, the antibacterial penam compounds of thisinvention are of use in human subjects and the daily dosages to be usedwill not differ significantly from other, clinically-used, penamantibiotics. The prescribing physician will ultimately determine theappropriate dose for a given human subject, and this can be expected tovary according to the age, weight, and response of the individualpatient, as well as the nature and the severity of the patient'ssymptoms, The compounds of this invention will normally be used orallyat dosages in the range from about 10 to about 200 mg. per kilogram ofbody weight per day, and parenterally at dosages from about 5 to about100 mg. per kilogram of body weight per day. These figures areillustrative only, however, and in some cases it may be necessary to usedosages outside these limits.

Certain of the compounds of this invention have the ability to formsolvates (e.g. hydrates), and all such hydrates are to be consideredwithin the scope and purview of the invention.

The following examples are provided solely for the purpose of furtherillustration. Infrared (IR) spectra are measured as potassium bromidediscs (KBr discs) or as Nujol mulls, and diagnostic absorption bands arereported in wave numbers (cm⁻¹). Nuclear magnetic resonance spectra(NMR) are measured at 60 MHz for solutions in deuterochloroform (CDCl₃),perdeutero dimethyl sulfoxide (DMSO-d₆) or deuterium oxide (D₂ O), andpeak positions are expressed in parts per million (ppm) downfield fromtetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate. Thefollowing abbreviations for peak shapes are used: s, singlet; d,doublet; t, triplet; q, quartet; m, multiplet.

PREPARATION 2-(3-[p-Methoxybenzimidoyl]ureido)acetyl ChlorideHydrochloride

A mixture of 8.96 g. of ethyl p-methoxybenzimidate, 6.45 g. of ethyl2-(isocyanato)acetate and 70 ml. of benzene is stirred at room temperature overnight, and then it is diluted with an excess of hexane. Thesolid which forms is filtered off and dried: 14.15 g., m.p. 84°-85.5° C.

To 14.10 g. of the above product in 175 ml. of ethanol, at -75° C., isadded 11 ml. of liquid ammonia. The cooling bath is then removed, andthe reaction mixture is stirred overnight. The solvent is removed byevaporation in vacuo, leaving an oil, which solidifies on triturationwith hexane. After drying, the solid weighs 12.2 g. and has m.p. 85°-88°C.

The latter solid is stirred with 300 ml. of 4 N hydrochloric acidovernight, to effect hydrolysis. The product is filtered off and driedgiving 11.05 g., m.p. 213°-215° C.

This latter product is stirred with 5.20 g. of phosphorus pentachloridein 125 ml. of methylene chloride overnight, and then the solid which isout of solution is filtered off. It is re-suspended in 125 ml. ofmethylene chloride, 5.20 g. of phosphorus pentachloride is added, and itis again stirred overnight. The solid is again filtered off, giving 5.22g. of 2-(3-[p-methoxybenzimidoyl]ureido)acetyl chloride hydrochloride,m.p. 146°-152° C. IR spectrum (Nujol mull): 1790 cm⁻¹.

In like manner, ethyl benzimidate is converted into2-(3-[benzimidoyl]ureido)acetyl chloride hydrochloride.

Ethyl 2-(p-chlorophenyl)acetimidate is converted into2-(3-[2-(p-chlorophenyl)acetimidoyl]ureido)acetyl chloride hydrochlorideusing the above procedure, except that the hydrolysis step is carriedout using 1 N sodium hydroxide and dimethoxyethane (3:1), followed byacidification with 4 N hydrochloric acid.

EXAMPLE I

The following ingredients are blended together in the indicatedproportions by weight.

    ______________________________________                                        Sucrose, U.S.P.    80.0                                                       Tapioca starch     13.5                                                       Magnesium stearate 6.5                                                        6-(D-2-Amino-2-phenyl                                                         acetamido)-2,2-dimethyl-                                                      3-(5-tetrazolyl)penam                                                                            100.0                                                      ______________________________________                                    

After the composition is thoroughly blended, tablets are punched fromthe mixture, each tablet being of such size as to contain 100 mg of thepenam compound.

Tablets are also prepared containing respectively 50 and 250 mg ofactive ingredient, by selecting the appropriate proportions of penamcompound and excipient blend in each case.

EXAMPLE II

The following ingredients are blended together in the indicatedproportions by weight.

    ______________________________________                                        Calcium carbonate    17.6                                                     Dicalcium phosphate  18.8                                                     Magnesium trisilicate                                                                              5.2                                                      Lactose, U.S.P.      5.2                                                      Potato starch        0.8                                                      6-(D-2-Amino-2-[3-thienyl]                                                    acetamido)-2,2-dimethyl-3-                                                    (5-tetrazolyl)penam  50.0                                                     ______________________________________                                    

The thoroughly-mixed pharmaceutical composition is filled into softgelatin capsules, such that each capsule contains 100 mg of activeingredient.

Capsules are also prepared containing respectively 50 and 250 mg ofactive ingredient by varying the proportions of penam compound andexcipient blend.

EXAMPLE III

The sodium salt of6-(D-2-amino-2-[p-hyroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamis thoroughly mixed and ground with sodium citrate (4% by weight). Theground, dry mixture is sterilized and packed into sterile vials, whichare then stoppered with serum caps under sterile conditions. When it isintended to use this preparation, sufficient sterile water is injectedinto the vials to dissolve the contents, and give a solution containing25 mg/ml of active ingredient. For parenteral use, the solution iswithdrawn from the vials using a hypodermic syringe.

In a similar manner, by varying the amount of water added, solutionscontaining respectively 10, 50, 100, and 200 mg/ml of active ingredientare prepared.

EXAMPLE IV6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-5-yl)penam

6-(Triphenylmethylamino)-2,2-dimethyl-3-(N-[4-methoxybenzyl]carbamoyl)penam--Toa stirred slurry of 216 g. of 6-aminopenicillanic acid in 1,500 ml. ofanhydrous chloroform is added 278 ml. of triethylamine, and the mixtureis then stirred at ambient temperature until a clear solution isobtained. This requires about 15 minutes. The solution is cooled toabout 0° C., and then 306 g. of triphenylmethyl chloride is added. Thestirring is continued at about 0° C. for 30 minutes, and then at ambienttemperature for a further 24 hours. The mixture is cooled to about 0° C.again, and 14 ml. of triethylamine, followed by 95 ml. of ethylchloroformate, is added. During this process the temperature rises toabout 15° C., and a precipitate forms. To facilitate stirring a further200 ml. of chloroform is added. The stirring is continued for 30minutes. Then, at about 0° C., 50 ml. of 4-methoxybenzylamine (availablefrom the Aldrich Chemical Company, Inc.) is injected into the reactionmedium, below the surface of the solvent. At 10 minute intervals, threefurther aliquots of 4-methoxybenzylamine (35 ml., 25 ml. and 21 ml.) areinjected in the reaction in similar fashion. The total volume of4-methoxybenzylamine added is 131 ml. The cooling bath is then removed,and the reaction is stirred for a further 1 hour. The chloroformsolution is washed successively with five 2,000-ml. portions of waterand one 2,000-ml. portion of saturated brine. The chloroform is finallydried using anhydrous sodium sulfate.

Examination of the reaction mixture at this point by NMR spectroscopy,reveals that the conversion into amide is approximately 85% complete.Accordingly, the chloroform solution is cooled in an ice-bath and 21 ml.of triethylamine, followed in about 5 minutes by 14.2 ml. of ethylchloroformate, is added. After a further 15 minutes, 9.8 ml. of4-methoxybenzylamine is added, and then in another 5 minutes a further9.8 ml. of 4-methoxybenzylamine is added. The reaction is concentratedin vacuo giving6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-methoxybenzyl]carbamoyl)penam,as an amorphous solid.

6-(Triphenylmethylamino)-2,2-dimethyl-3-(chloro-[N-(4-methoxybenzyl)imino]methyl)penam--Theamide described above is dissolved in 480 ml. of pyridine, and then thesolution is cooled to about -5° C. To this solution is added dropwise,with stirring during 10 minutes, 108 ml. of thionyl chloride. Thereaction mixture is then allowed to warm slowly to ambient temperaturefor a further 21 hours. All the volatile components are removed in vacuoleaving the crude imino chloride as an amorphous solid. The NMR spectrum(in CHCl₃) of this product shows absorption bands at 4.70 ppm (singlet,C-3 hydrogen), 4.65 ppm (singlet, benzyl hydrogens), 4.30-4.60 ppm(multiplet, C-5 and C-6 hydrogens), 3.75 ppm (singlet, methoxyhydrogens), 1.57 ppm (singlet, C-2 methyl hydrogens) and 1.38 ppm(singlet, C-2 methyl hydrogens).

6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-5-yl)penam--Theimino chloride described above is re-dissolved in 500 ml. of chloroformand then the solution is cooled to about -5° C. in an ice-salt bath. Tothe solution is then added, with stirring, 160 ml. of trimethylsilylazide (available from the Aldrich Chemical Company, Inc.). After beingallowed to warm to ambient temperature, the reaction mixture is stirredfor a further 22 hours. It is then cooled to about 0° C. and 2,000 ml.of 1.5 N sodium hydroxide solution is added, followed by sufficientadditional 1.5 N sodium hydroxide to bring the pH of the aqueous to 6.0.The aqueous phase is separated off, and the chloroform phase is washedsuccessively with five 2,000-ml. portions of water and one 500-ml.portion of saturated brine. The chloroform is then dried by filtrationthrough anhydrous sodium sulfate, and finally concentrated to dryness.The residue is triturated with 1,000 ml. of ether, and then filteredoff. This affords 150 g. of crude product, m.p. 174°-178° C. The crudeproduct is purified by re-dissolving it in chloroform and filtering thesolution through chromatographic grade silica gel. The chloroform isremoved by evaporation in vacuo, and the residue is again trituratedwith ether. This affords 128 g. of6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-5-yl)penamas a light tan solid, m.p. 193°-195° C. The infrared spectrum (KBr disc)of the product shows an absorption band at 1790 cm⁻¹ (β-lactamcarbonyl). The NMR spectrum (in CDCl₃) shows absorption bands at 7.25ppm (multiplet, aromatic hydrogens), 5.50 ppm (broad singlet, benzylhydrogens, 5.05 ppm (singlet, C-3 hydrogen), 4.40 ppm (broad singlet,C-5 and C-6 hydrogens), 3.80 ppm (singlet, methoxy hydrogens), 1.45 ppm(singlet, C-2 methyl hydrogens) and 0.70 ppm (singlet, C-2 methylhydrogens).

EXAMPLE V

The following compounds are prepared by repeating the procedure ofExample IV, except that where necessary the triphenylmethyl chloride isreplaced by an equimolar amount of the appropriately-substitutedtriphenylmethyl chloride, and where necessary the 4-methoxybenzylamineis replaced by an equimolar amount of the requisite amine.

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-benzyltetrazol-5yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[2-methoxybenzyl]tetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-isopropoxybenzyl]tetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[3-chlorobenzyl]tetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-2-(1-[3-methylbenzyl]tetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[3-chloro-4-methoxybenzyl]tetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam,

6-(diphenyl-3-tolylmethylamino)-2,2-dimethyl-3-(1-[4-ethoxybenzyl]tetrazol-5-yl)penam,and

6-(diphenyl-2-methoxyphenylmethylamino)-2,2-dimethyl-3-(1-[4-phenylbenzyl]tetrazol-5-yl)penam,

respectively.

Substituted triphenylmethyl chlorides are prepared according toprocedures well known in the art. See "Organic Syntheses", John Wiley &Sons,Inc., 1955, Collective Volume 3, pages 839-846.

EXAMPLE VI

The following compounds are prepared by repeating the procedure ofExample IV, except that where necessary the triphenylmethyl chloride isreplaced by an equimolar amount of the appropriately-substitutedtriphenylmethyl chloride, and where necessary the 4-methoxybenzylamineis replaced by an equimolar amount of the requisite amine.

6-(diphenyl-4-bromophenylmethylamino)-2,2-dimethyl-3-(1-[2-thienylmethyl]tetrazol-5-yl)penam,

6-(di[4-methoxyphenyl]phenylmethylamino)-2,2-dimethyl-3-(1-benzyltetrazol-5-yl)penam,

6-(di[3-chlorophenyl]phenylmethylamino)-2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-5-yl)penam,

6-(di[2-tolyl]phenylmethylamino)-2,2-dimethyl-3-(1-[2,4-dimethoxybenzyl]tetrazol-5-yl)penam,

6-(tri[3-ethoxyphenyl]methylamino)-2,2-dimethyl-3-(1-[4-ethylbenzyl]tetrazol-5-yl)penam,and

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[5-methylfurfuryl]tetrazol-5-yl)penam,

respectively.

Substituted triphenylmethyl chlorides are prepared according toprocedures well known in the art. See "Organic Syntheses", John Wiley &Sons, Inc., 1955, Collective Volume 3, pages 839-846.

EXAMPLE VII6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam

6-(Triphenylmethylamino)-2,2-dimethyl-3-(N-4-benzyloxybenzyl]carbamoyl)penam--Toa stirred solution of 20.0 g. of 6-triphenylmethylamino-penicillanicacid (Sheehan and Henery-Logan, Journal of the American ChemicalSociety, 81, 5836 [1959]) in 140 ml. of acetone, at 0°-5° C., is added6.08 ml. of triethylamine followed by 5.78 ml. of isobutylchloroformate. After a further 10 minutes, the mixture is filtereddirectly into a stirred solution of 9.28 g. of 4-benzyloxybenzylamine in1,000 ml. of water and 300 ml. of acetone at ambient temperature. Themixture so obtained is stirred for 4 minutes, and then an additional 500ml. of water is added. Stirring is continued for a further 7 minutes,and then the reaction mixture is extracted with ether. The ether isdried using anhydrous magnesium sulfate, and then evaporated to drynessin vacuo. The crude product so obtained is re-dissolved in 200 ml. ofether, which is then added dropwise over 10 minutes to 2,500 ml. ofhexane. The solid which precipitates is filtered off, giving 21.5 g. of6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-benzyloxybenzyl]carbamoyl)penam.

6-(Triphenylmethylamino)-2,2-dimethyl-3-(chloro-[N-(4-benzyloxybenzyl)imino]methyl)penam--Toa stirred solution of 2.0 g. of the above-described amide in 10 ml. ofdry chloroform, at 0°-5° C., is added 0.99 ml. of pyridine, followed by5.42 ml. of a 2.26 M solution of phosgene in chloroform. The reactionmixture is then stirred at ambient temperature overnight. At this point,it is evaporated to dryness in vacuo, yielding a viscous gum, which isextracted with 100 ml. of ether. The ether is filtered, and evaporationof the filtrate affords the imino chloride as a yellow foam.6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam--Theabove-described imino chloride is re-dissolved in 8 ml. of dryN,N-dimethylformamide. To this solution is added 249 mg. of potassiumazide, and the turbid solution is stirred at ambient temperature for2.25 hours. The solvent is evaporated at ambient temperature, under highvacuum, leaving a brown gum. This residue is partitioned between 60 ml.of water and 150 ml. of ether. The ether phase is separated off, washedwith saturated brine, dried using anhydrous sodium sulfate, and finallyevaporated to dryness in vacuo. The residue is 980 mg. of6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam.Its NMR spectrum (in CDCl₃) shows absorption bands at 7.30 ppm(multiplet, aromatic hydrogens), 5.45 ppm (quartet, benzyl hydrogens),5.05 ppm (singlet, C-3 hydrogen), 5.00 ppm (singlet, benzyl hydrogens),4.40 ppm (multiplet, C-5 and C-6 hydrogens), 1.40 ppm (singlet, C-2hydrogen) and 0.70 ppm (singlet, C-2 hydrogen).

EXAMPLE VIII

The procedure of Example VII is repeated, except that the4-benzyloxybenzylamine used therein is replaced by an equimolar amountof the appropriate amine, to produce the following congeners:

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-n-hexyloxybenzyl]tetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-fluorobenzyl]tetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-isopropylbenzyl]tetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[3,4-dimethoxybenzyl]tetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[3,5-dichlorobenzyl]tetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[3-chloro-4-ethoxybenzyl]tetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[5-methyl-2-thienyl)methyl]tetrazol-5-yl)penam,and

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[3tolyl]tetrazol-5-yl)penam,

respectively.

EXAMPLE IX6-Triphenylmethylamino)-2,2-dimethyl-3-(1-[4-methoxybenzyl]-tetrazol-5-yl)penam(A)6-(Triphenylmethylamino)-2,2-dimethyl-3-(N-[4-methoxybenzyl]carbamoyl)penam.

To a stirred slurry of 86.4 g. (0.4 mole) of 6-aminopenici llanic acidin 600 ml. of anhydrous chloroform is added 111.2 ml. (0.8 mole) oftriethylamine, and the mixture is stirred at ambient temperature until aclear solution is obtained (ca. 15 minutes). To this solution is thenadded, portionwise over about 25 minutes, 134.9 g. (0.44 mole) of 90%pure triphenylmethyl chloride, at ambient temperature. Stirring iscontained for a further 64 hours, and then 5.6 ml. of triethylamine isadded. The solution is cooled to 0°-5° C., and then an ice-cold solutionof 38 ml (0.4 mole) of ethyl chloroformate in 80 ml. of chloroform isadded dropwise during 30 minutes with the reaction temperature beingmaintained between 4° and 9° C. After a further 15 minutes of stirring,52.4 ml. (0.4 mole) of 4-methoxybenzylamine is injected into thereaction medium, below the surface of the solvent, at 4° and 9° C., andover a period of 30 minutes. Stirring is continued for a further 30minutes at 3° to 6° C., for 20 minutes while the reaction medium warmsto 20° C. The reaction mixture is then washed with water, followed bybrine. Finally, it is dried using magnesium sulfate to give a chloroformsolution of6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-methylbenzyl]carbamoyl)penam

(B)6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[p-methoxybenzyl]tetrazol-5-yl)penam.

To a chloroform solution containing 69.4 g. (0.120 mole) of6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-methoxybenzyl]carbamoyl)penam, and having a volume of 133.3 ml., prepared by the methoddescribed in (A) above, is added a further 132.7 ml. of chloroform,followed by 29.1 ml. (0.360 mole) of pyridine. This solution is cooledto 10° C., and then 26.22 g. (0.216 mole) of phosphorus pentachloride isadded during 15 minutes, with stirring. Stirring is continued at ca. 10°C. for 10 minutes, and then at ambient temperature for a further 1.5hours, giving a solution of the imino chloride. To a one-sixth aliquotof this imino chloride solution is added 4.85 ml. (0.060 mole) ofpyridine, followed by 2.42 ml. (0.060 mole) of methanol at ca. 25° C.,with stirring. After a further 15 minutes of stirring 2.03 g. (0.038mole) of ammonium chloride, followed by 2.59 g (0.039 mole) of 95% puresodium azide, is added. The reaction mixture is then stirred at ambienttemperature for a further 4 hours. At this point, 400 ml, of water and200 ml. of chloroform are added, and then the layers are separated. Theorganic phase is washed with water, dried using magnesium sulfate, andthen concentrated to a small volume in vacuo. This final chloroformsolution is added dropwise with stirring to a large volume ofdiisopropylether, and, after 30 minutes, the precipitate which hasformed is filtered off. This affords 6.1 g. of6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-5-yl)penam.The infrared spectrum of the product (KBr disc) shows an absorption bandat 1790 cm⁻¹ (β-lactam); and the NMR spectrum (in CDCl₃) showsabsorptions at 7.25 ppm (multiplet, aromatic hydrogens, 5.40 ppm (broadsinglet, benzyl hydrogens), 5.05 ppm (singlet, C-3 hydrogen), 4.50-4.30ppm (multiplet, C-5 and C-6 hydrogens), 3.70 ppm (singlet, methoxyhydrogens), 3.50-3.10 ppm (broad peak, NH), 1.50 ppm (singlet, C-2methyl hydrogens) and 0.75 ppm (singlet, C-2 methyl hydrogens).

EXAMPLE X

When the procedure of Example IX is repeated, and the4-methoxybenzylamine used therein is replaced by an equimolar amount ofthe appropriate amine, the following compounds are obtained;

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-ethoxybenzyl]-tetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[3-chloro-4-methoxybenzyl]tetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam,

respectively.

EXAMPLE XI6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam(A) 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-furfurylcarbamoyl)penam.

To a stirred slurry of 216 g. (1 mole) of 6-aminopenicillanic acid in1500 ml. of chloroform, is added, at 25°-30° C., 278 ml. (2 mole) oftriethylamine. To the solution thus obtained is added, portionwiseduring 25 minutes, 306 g. (1.1 mole) of triphenylmethyl chloride, at25°-30° C. Stirring is then continued for 44 hours at ambienttemperature.

A 522-ml. portion (0.25 mole) of the above6-(triphenylmethylamino)-penicillanic acid solution is cooled to 4° C.,and then 3.5 ml. of triethylamine is added. With vigorous stirring isthen added 23.75 ml. of ethyl chloroformate at 5°-10° C. Stirring iscontinued for a further 30 minutes at ca. 6° C. at the end of theaddition, and then 8.43 ml. of furfurylamine is injected into thereaction medium below the surface of the solvent. At 10 minuteintervals, three further portions of furfurylamine (5.90 ml., 4.22 ml.and 3.54 ml.) are then injected into the reaction medium in similarfashion. The total volume of furfurylamine added is 22.09 ml. (0.25mole), and the temperature is maintained at ca. 6° C. throughout theaddition of the amine. When the addition of the amine is complete, thecooling bath is removed and the reaction medium is stirred at ca. 25° C.for 45 minutes. In is then washed successively with three portions ofwater, and one portion of brine. Finally, it is dried using anhydrousmagnesium sulfate. This affords 610 ml. of a chloroform solution of6-(triphenylmethylamino)-2,2-dimethyl-3-(N-furfurylcarbamoyl)penam. TheNMR spectrum of this solution showed absorptions at 7.3 ppm (17H, m),6.2 ppm (1H, m), 4.35 ppm (3H, m), 4.05 ppm (2H, s), 1.6 ppm (3H, s) and1.35 (3H, s).

(B)6-(triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam.

To a stirred solution of 3.05 g. (5.7 mmole) of6-(triphenylmethylamino)-2,2-dimethyl-3-(N-furfurylcarbamoyl)penam, in 8ml. of chloroform, at 0° C., is added 1.35 ml. (17 mmole) of pyridine,followed by 2.64 ml. of a 4.33 M solution of phosgene in chloroform.Stirring is then continued for 1 hour at 25° C. The chloroform, andexcess phosgene and pyridine, are then removed by evaporation in vacuo,and the residue is redissolved in 5 ml. of chloroform. The solution iscooled to 0° C., and then 2.25 g. (14.4 mmole) of tetramethylguanidiniumazide is added in several small portions. Stirring is continued for 15minutes at ambient temperature, and then 20 ml. of chloroform, followedby 30 ml. of water, are added and the pH is adjusted to 6.5. Thechloroform layer is separated off, washed with water, followed by brine,and then dried (MgSO₄). Removal of the solvent by evaporation in vacuoleaves 3.37 g. of a dark-red foam. The foam is re-dissolved in a smallvolume of chloroform and absorbed onto a column of chromatrographicsilica gel. Elution of the column with chloroform, followed byevaporation of the appropriate fractions in vacuo, affords6-(triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl) penam.The NMR spectrum of the product (CDCl₃) shows absorptions at 7.40 ppm(m, 16H), 6.40 ppm (m, 2H) 5.50 ppm (s, 2H), 5.20 ppm (s, 1H), 4.90 ppm(m, 2H), 1.60 ppm (s, 3H), and 0.80 ppm (s, 3H).

EXAMPLE XXII

The procedure of Example XXI is repeated, except that where necessarythe triphenylmethyl chloride used therein is replaced by an equimolaramount of the appropriately-substituted triphenylmethyl chloride, andwhere necessary the furfuryl amine is replaced by the requisite amine,to produce the following congeners:

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-benzyltetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[5-methylfurfuryl]tetrazol-5-yl)penam,

6-(diphenyl-3-chlorophenylmethylamino)-2,2-dimethyl-3-(1-[4-iodobenzyl]tetrazol-5-yl)penam,

6-(diphenyl-2-fluorophenylmethylamino)-2,2-dimethyl-3-(1-[4-tolylmethyl]tetrazol-5-yl)penam,

6-(diphenyl-2-methoxyphenylmethylamino)-2,2-dimethyl-3-(1-[4-biphenylylmethyl]tetrazol-5-yl)penam,

6-(diphenyl-4-tolylmethylamino)-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam,

6-(diphenyl-4-chlorophenylmethylamino)-2,2-dimethyl-3-(1-[3,4-diethoxybenzyl]tetrazol-5-yl)penam,

6-(diphenyl-4-isopropylphenylmethylamino)-2,2-dimethyl-3-(1-[2-methoxybenzyl]tetrazol-5-yl)penam,

6-(diphenyl-4-n-butylphenylmethylamino)-2,2-dimethyl-3-(1-[4-isopentylbenzyl]tetrazol-5-yl)penam,

6-(diphenyl-3-isopropoxyphenylmethylamino)-2,2-dimethyl-3-(1-[3-chloro-4-ethoxybenzyl]tetrazol-5-yl)penam,

6-(diphenyl-3-n-butoxyphenylmethylamino)-2,2-dimethyl-3-(1-[3-n-pentyloxy-4-benzyloxybenzyl]tetrazol-5-yl)penam,

6-(tri[3-methoxyphenyl]methylamino)-2,2-dimethyl-3-(1-[4-n-hexylbenzyl]tetrazol-5-yl)penamand

6-(tri[4-biphenylyl]methylamino)-2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-5-yl)penam,

respectively.

EXAMPLE XIII6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[4-hydroxybenzyl]tetrazol-5-yl)penam(A)6-(Triphenylmethylamino)-2,2-dimethyl-3-(N-[4-hydroxybenzyl]carbamoyl)penam

To a stirred slurry of 43.2 g. (0.20 mole) of 6-aminopenicillanic acidin 300 ml. of chloroform is added 55.6 ml. (0.40 mole) of triethylamine,followed by 61.2 g. (0.22 mole) of triphenylmethyl chloride, at ambienttemperature. Stirring is then continued for a further 48 hours atambient temperature.

A 120-ml. portion (containing 0.060 mole of triethylammonium6-[triphenylmethylamino]penicillanate) of the above chloroform solutionis withdrawn. It is diluted with a further 40 ml. of chloroform, andthen 1.67 ml. (0.012 mole) of triethylamine is added. The mixture iscooled to ca. 4° C., in an ice-bath, and then 6.84 ml. of ethylchloroformate is added all at once, with stirring. Stirring is continuedfor 30 minutes with ice-bath cooling, and then 7.5 g. (0.060 mole) of4-hydroxybenzylamine is added. Stirring is continued for 10 minutes withice-bath cooling, and then for a further 1 hour without cooling. At thispoint, the chloroform solution is washed with water, followed by brine,and then dried using anhydrous sodium sulfate. Removal of the solvent byevaporation in vacuo affords the crude amide. The crude amide isre-dissolved in 50 ml. of chloroform and absorbed on a column ofchromatographic grade silica gel. The column is eluted with chloroform,taking 400 ml. fractions. Fractions 9 to 15 are combined andconcentrated to an oil, which solidifies on trituration with methylenechloride. After further trituration with ether, there is obtained 12.63g. of6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-hydroxybenzyl]carbamoyl)penam,m.p. 166°-168° C. (dec.). The infrared spectrum of the product (CHCl₃solution) shows absorptions at 1785 cm⁻¹ (β-lactam) and 1675 cm⁻¹ (amideI). The NMR spectrum of the product (CDCl₃) shows absorptions at7.60-6.40 ppm (multiplet, 20H, aromatic hydrogens and amide hydrogen),4.70-4.10 ppm (multiplet, 5H, C-5 and C-6 hydrogens, benzyl methylenehydrogens and C-3 hydrogen), 2.98 ppm (doublet, 1H, amine nitrogen),1.64 ppm (singlet, 3H, C-2 methyl hydrogens) and 1.31 ppm (singlet, 3H,C-2 methyl hydrogens).

(B)6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[4-hydroxybenzyl]tetrazol-5-yl)penam.

To a stirred solution of 1.69 g. (3 m mole) of6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-hydroxybenzyl]carbamoyl)penam(prepared as described in A) in 9 ml. of chloroform is added 1 ml. (12mmole) of pyridine. The solution is cooled to ca. 4° C. in an ice-bathand 0.80 ml. of chlorotrimethylsilane is added. The solution is stirredfor 40 minutes at ambient temperature, and then it is again cooled toca. 4° C. Phosgene (1.5 ml. of a 4.3 M solution in chloroform (6.45mmole) is added and the cooling bath is removed. Stirring is continuedfor a further 1.5 hours, and then all the volatile components areremoved by evaporation in vacuo.

The oily residue is redissolved in 6 ml. of chloroform and the solutionis cooled to ca. 4° C. in an ice-bath. To the stirred solution is added0.95 g. (6 mmole) of tetramethylguanidinium azide, and then stirring iscontinued for a further 1 hour at ambient temperature. At this point, 25ml. of water is added, followed by sufficient 1 N sodium hydroxide tobring the pH of the aqueous phase to 10. The chloroform layer isseparated off, washed with water, dried using sodium sulfate, andevaporated to dryness in vacuo. The oily residue (2.3 g.) is dissolvedin a small volume of chloroform and absorbed on a column of 30 g. ofchromatographic silica gel. The column is eluted with chloroform, taking50-ml. fractions. Fractions 13 to 19 are combined and concentrated invacuo to give 0.71 g. of6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-hydroxybenzyl]tetrazol-5-yl)penam.The infrared spectrum of the product (in CHCl₃) shows an absorption at1780 cm⁻¹ (β-lactam). The NMR spectrum (CDCl₃) shows absorptions at7.80-6.67 ppm (multiplet, 20H, aromatic hydrogens and phenolichydrogen), 5.66-5.10 ppm (quarter, 2H, benzyl methylene hydrogens), 5.02ppm (singlet, 1H, C-3 hydrogen), 4.60-4.20 ppm (multiplet, 2H, C-5 andC-6 hydrogen), 3.10 ppm (doublet, 1H, amine hydrogen), 1.44 ppm(singlet, 3H, C-2 methyl hydrogens) and 0.71 ppm (singlet, 3H, C-2methyl hydrogens).

EXAMPLE XIV

The procedure of Example XIII is repeated, except that where necessarythe triphenylmethyl chloride is replaced by theappropriately-substituted triphenylmethyl chloride, and where necessarythe 4-hydroxybenzylamine is replaced by the requisite amine, to producethe following congeners:

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[2-hydroxybenzyl]tetrazol-5-yl)penam,

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[3-hydroxybenzyl]tetrazol-5-yl)penam,

6-(diphenyl-[3-methoxyphenyl]methylamino)-2,2-dimethyl-3-(1-[4-hydroxybenzyl]tetrazol-5-yl)penam,

6-(di[4-chlorophenyl]phenylmethylamino)-2,2-dimethyl-3-(1-[4-hydroxybenzyl]tetrazol-5-yl)penam,

6-(tri[4-tolyl]methylamino)-2,2-dimethyl-3-(1-[4-hydroxybenzyl]tetrazol-5-yl)penam,and

6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-hydroxy-3-methylbenzyl]tetrazol-5-yl)penam,

respectively.

EXAMPLE XV6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[5-methylfurfuryl]tetrazol-5-yl)penam

The title compound is prepared according to the procedure of Example XI,but using 5-methylfurfurylamine in place of furfurylamine. The NMRspectrum (CDCl₃) of the product shows absorptions at 7.36 ppm (m, 15H),6.33 ppm (m, 1H), 5.93 ppm (m, 1H), 5.50 ppm (s, 2H), 5.20 ppm (s, 1H),4.50 ppm (m, 2H), 3.23 ppm (d, 1H), 2.26 ppm (s, 3H), 1.63 (ppm (s, 3H)and 0.90 ppm (m, 3H).

EXAMPLE XVI6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[2,4-dimethoxybenzyl]tetrazol-5-yl)penam.

The title compound is prepared in 46% overall yield from6-(triphenymethylamino)penicillanic, by replacing the furfurylamine ofExample XI by 2,4-dimethoxybenzylamine. The crude product is purified byrecrystallization from a mixture of methylene chloride and methanol. TheNMR spectrum of the product (CDCl₃) shows absorptions at 7.40 ppm (m,16H), 6.45 ppm (m, 2H), 5.40 ppm (s, 2H), 4.50 ppm (m, 2H), 3.75 ppm (s,3H), 3.70 ppm (s, 3H), 1.55 ppm (s, 3H) and 0.90 (s, 3H).

EXAMPLE XVII6-Amino-2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-5-yl)penamp-toluenesulfonate

To a stirred slurry of 143 g. of6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-5-yl)penamin 1,000 ml. of dry acetone is added 45.0 g. of p-toluenesulfonic acidmonohydrate, at ambient temperature. The solids slowly dissolve, givinga clear solution. After about 15 minutes, the product starts toprecipitate. Stirring is continued for a further 45 minutes after theproduct starts to appear, and then a first crop of product is filteredoff and washed with chloroform. The acetone is evaporated to dryness,and the solid residue is slurried for 45 minutes in 300 ml. ofchloroform. This affords a second crop of product. The two crops arecombined, slurried for 1 hour in 1,000 ml. of chloroform, filtered off,and dried in vacuo giving 123 g. of6-amino-2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-5-yl)penamp-toluenesulfonate, m.p. 174°-175.5° C. The infrared spectrum (KBr disc)of the product shows an absorption band at 1795 cm⁻¹ . The NMR spectrum(in DMSO-d₆) shows absorption bands at 7.20 ppm (multiplet, aromatichydrogens), 5.80 ppm (multiplet, benzyl hydrogens, C-5 hydrogen and C-3hydrogens), 5.20 ppm (doublet, C-6 hydrogen), 3.75 ppm (singlet, methoxyhydrogens, 2.35 ppm (singlet, sulfonate methyl hydrogens), 1.70 ppm(singlet, C-2 methyl hydrogens) and 0.85 ppm (singlet, C-2 methylhydrogens).

EXAMPLE XVIII

By reacting the appropriate6-(triphenylmethylamino)-2,2-dimethyl-3-(1-substitutedtetrazol-5-yl)penam or 6-(substitutedtriphenylmethylamino)-2,2-dimethyl-3-(1-substituted tetrazol-5-yl)penam,chosen from those in Examples V to VIII and X to XVI, withp-toluenesulfonic acid, according to the procedure of Example XVII, thefollowing compounds are obtained as their p-toluenesulfonate salts:

6-amino-2,2-dimethyl-3-(1-benzyltetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[2-methoxybenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[4-isopropoxybenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[3-chlorobenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[3-chloro-4-methoxybenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[4-ethoxybenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[4-phenylbenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[2-thienylmethyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[3-tolyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[2,4-dimethoxybenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[4-n-hexyloxybenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[4-fluorobenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[3,4-dimethoxybenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[4-isopropylbenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[(5-methyl-2-thienyl)methyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[5-methylfurfuryl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[4-iodobenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[4-biphenylylmethyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[4-n-hexylbenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[4-hydroxybenzyl]tetrazol-5-yl)penam, and

6-amino-2,2-dimethyl-3-(1-[2-hydroxybenzyl]tetrazol-5-yl)penam,

respectively.

EXAMPLE XIX6-Amino-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam

A solution consisting of 558 mg. of6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam,156 mg. of p-toluenesulfonic acid monohydrate and 1 ml. of acetone isstored at ambient temperature for 2.5 hours. It is then added withstirring to 50 ml. of ether. After stirring for a further 10 minutes,the solid which has precipitated is filtered off. This affords 394 mg.of the p-toluenesulfonate of the product. A 304-mg. aliquot of thisp-toluenesulfonate salt is dissolved in 10 ml. of methylene chloride,and to the solution is added 69.7 μl. of triethylamine. After 3 minutes,5 ml. of water are added and the mixture is stirred vigorously. Theorganic phase is then separated off, diluted with ether, dried usinganhydrous magnesium sulfate, and evaporated to dryness in vacuo. Theresidue is 189 mg. (69% yield) of2-amino-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam. TheNMR spectrum (in CDCl₃) of the product shows absorption bands at 7.40ppm (singlet, phenyl hydrogens), 7.15 ppm (quartet, phenylenehydrogens), 5.55 ppm (broad singlet, C-5 and benzyl hydrogens), 5.20 ppm(singlet, C-3 hydrogens), 5.10 ppm (singlet, benzyl hydrogens), 4.60 ppm(doublet, C-6 hydrogen), 1.50 ppm (singlet, C-2 methyl hydrogens) and0.90 ppm (singlet, C-2 hydrogens).

EXAMPLE XX 6-Amino-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam

To a stirred solution of 0.422 g. (0.75 mmole) of6-(triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penamin 1 ml. of acetone at ambient temperature, is added 0.142 g. (0.75mmole) of p-toluenesulfonic acid monohydrate. Stirring is continued for30 minutes, and then the solvent is removed by evaporation in vacuo.This affords the title compound as its p-toluenesulfonate salt. IR(Nujol mull): 1780 cm⁻¹ (β-lactam). NMR (DMSO-d₆): 7.20 ppm (q, 4H),6.40 ppm (m, 2H), 5.90 ppm (s, 2H), 5.60 ppm (m, 2H), 5.00 ppm (d, 1H),2.20 ppm (s, 3H), 1.60 ppm (s, 3H), 0.80 ppm (s, 3H).

EXAMPLE XXI6-Amino-2,2-dimethyl-3-(1-[5-methylfurfuryl]tetrazol-5-yl)penam

To a stirred solution of 1.827 g. of6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[5-methylfurfuryl]tetrazol-5-yl)penamin 3 ml. of acetone is added a solution of 0.59 g. of p-toluenesulfonicacid monohydrate in 2 ml. of acetone. The mixture is stirred at ambienttemperature for 30 minutes, and then the precipitate which has formed isfiltered off. This affords 0.87 g. (54% yield) of the title compound asits p-toluenesulfonate salt. The NMR spectrum of the product (CDCl₃)shows absorptions at 7.28 ppm (q, 4H), 6.50 ppm (d, 1H), 6.01 ppm (s,1H), 5.86 ppm (s, 2H), 5.71 ppm (s, 1H), 5.68 ppm (d, 1H), 5.09 ppm (d,1H), 2.00 ppm (2s, 6H), 1.66 ppm (s, 3H) and 0.88 ppm (s, 3H).

EXAMPLE XXII6-Amino-2,2-dimethyl-3-(1-[2,4-dimethoxybenzyl]tetrazol-5-yl)penam

To a stirred solution of 2.0 g. of6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[2,4-dimethoxybenzyl]tetrazol-5-yl)penamin 40 ml. of methylene chloride, is added a solution of 0.600 g. ofp-toluenesulfonic acid monohydrate in 4 ml. of acetone. The resultingclear solution is stirred at ambient temperature for 18 hours, and thenthe solvent is removed by evaporation in vacuo. The residue istriturated with ether, to give 1.76 g. (99% yield) of a white solid,which is the title compound as its p-toluenesulfonate salt. The NMRspectrum (DMSO-d₆) shows absorptions at 7.65 ppm (m, 5H), 6.90 ppm (m,2H), 5.95 ppm (m, 3H), 5.40 ppm (d, 1H), 3.95 ppm (s, 3H), 2.45 ppm (s,3H), 1.95 ppm (s, 3H) and 1.15 ppm (s, 3H).

EXAMPLE XXIII 6-Amino-2,2-dimethyl-3-(5-tetrazolyl)penam

A stirred solution of 32.0 g. of6-amino-2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-5-yl)penamp-toluenesulfonate, and 24 ml. of anisole, in 96 ml. of trifluoroaceticacid is maintained at 40±1° C. for 35 minutes. The trifluoroacetic acidis then removed rapidly by vacuum distillation. A 120-ml. portion ofether is added to the residue, which produces a white flocculentsuspension. The suspension and solvent is cooled to about 0° C., and toit is then added, portionwise, 80 ml. of 2 N sodium hydroxide, givingtwo clear phases. The pH of the aqueous phase at this point is about2.7. The layers are separated, and the ether phase is discarded. The pHof the aqueous phase is raised to 4.1 with 2 N sodium hydroxide. Thisaqueous phase is then washed with 100 ml. of ether and filtered. It iscombined with the corresponding aqueous phases from four other identicalexperiments, and the total aqueous solution is lyophilized to give crude6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam. This crude product isslurried in a small amount of water and filtered off. It is thenre-suspended in water and brought into solution by raising the pH to 7.4by the addition of sodium hydroxide solution. The clear solution isextracted with ether and the extracts are discarded. The pH of theaqueous phase is adjusted to 4.1 using dilute hydrochloric acid, and theproduct which precipitates is filtered off. The infrared spectrum of theproduct shows an absorption at 1795 cm⁻¹. Its NMR spectrum (in DMSO-d₆)shows absorptions at 5.65 ppm (doublet C-5 hydrogen), 5.20 ppm (singlet,C-3 hydrogen), 4.70 ppm (doublet, C-6 hydrogen), 1.65 ppm (singlet, C-2methyl hydrogens) and 1.10 ppm (singlet, C-2 methyl hydrogens).

EXAMPLE XXIV

Reaction of the p-toluenesulfonate salt of a6-amino-2,2-dimethyl-3-(1-substituted tetrazol-5-yl)penam, selectedfrom:

6-amino-2,2-dimethyl-3-(1-[2-methoxybenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[4-isopropoxybenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[3-chloro-4-methoxybenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[4-ethoxybenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[4-phenylbenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[2-thienylmethyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[4-n-hexyloxybenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[3,4-dimethoxybenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[5-methyl-2-thienyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[5-methylfurfuryl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[4-biphenylmethyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[2,4-dimethoxybenzyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[4-hydroxybenzyl]tetrazol-5-yl) penam,

6-amino-2,2-dimethyl-3-(1-[2-hydroxybenzyl]tetrazol-5-yl)penam,

with trifluoroacetic acid and anisole, according to the procedure ofExample XXIII, produces 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam ineach case.

EXAMPLE XXV 6-(Triphenylmethylamino)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 1.69 g. (3 m mole) of6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-hydroxybenzyl]carbamoyl)penamprepared as described in Example XIII in 9 ml. of chloroform is added 1ml. (12 mmole) of pyridine. The solution is cooled to ca. 4° C. in anice-bath and 0.80 ml. of chlorotrimethylsilane is added. The solution isstirred for 40 minutes at ambient temperature, and then it is againcooled to ca. 4° C. Phosgene (1.5 ml. of a 4.3 M solution in chloroform6.45 mmole) is added and the cooling bath is removed. Stirring iscontinued for a further 1.5 hours, and then all the volatile componentsare removed by evaporation in vacuo. The oily residue is redissolved in6 ml. of chloroform and the solution is cooled to ca. 4° C. in anice-bath. To the stirred solution is added 0.95 g. (6 mmole) oftetramethylguanidinium azide, and then stirring is continued for afurther 1 hour at ambient temperature. At this point, 25 ml. of water isadded, followed by sufficient 1 N sodium hydroxide to bring the pH ofthe aqueous phase to 10. The chloroform layer is removed, washed withwater, dried using sodium sulfate, and evaporated to dryness in vacuo.This affords crude6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-trimethylsilyloxybenzyl]tetrazol-5-yl)penam,which is purified by chromatography on silica gel using chloroform aseluant.

To a stirred solution of 200 mg. of the purified trimethylsilyloxybenzylderivative, in 4 ml. of tetrahydrofuran, is added 0.3 ml. of 1.0 Nsodium hydroxide. The solution is stirred at ambient temperature for 50minutes, and then the pH is adjusted to 5.7 using 5% hydrochloric acid.The solvent is removed by evaporation in vacuo to yield crude6-(triphenylmethylamino)-2,2-dimethyl-3-(5-tetrazolyl)penam.

EXAMPLE XXVI

When the procedure of Example XXV is repeated, but using as startingmaterial6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[2-hydroxybenzyl]carbamoyl)penam,there is produced6-(triphenylmethylamino)-2,2-dimethyl-3-(5-tetrazolyl)penam.

The6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[2-hydroxybenzyl]carbamoyl)penamis prepared according to the procedure of Example XIII, Part A, butusing 2-hydroxybenzylamine in place of 4-hydroxybenzylamine.

EXAMPLE XXVII

Starting with the appropriate 6-(substitutedtriphenylmethylamino)-2,2-dimethyl-3-(N-[4-hydroxybenzyl]carbamoyl)penam,and following the procedure of Example XXV, there is obtained thefollowing congeners:

6-(diphenyl-[3-methoxyphenyl]methylamino)-2,2-dimethyl-3-(5-tetrazol-5-yl)penam,

6-(diphenyl-[2-fluorophenyl]methylamino)-2,2-dimethyl-3-(5-tetrazol-5-yl)penam,

6-(di[4-chlorophenyl]phenylmethylamino)-2,2-dimethyl-3-(5-tetrazol-5-yl)penamand

6-(tri[4-tolyl]methylamino)-2,2-dimethyl-3-(5-tetrazolyl)penam,

respectively.

The starting materials used in this Example are prepared by the methodof Example XIII, Part A, but using the appropriately-substitutedtriphenylmethyl chloride.

EXAMPLE XXVIII6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[ethoxycarbonyl]tetrazol-5-yl)penam(A)6-(Triphenylmethylamino)-2,2-dimethyl-3-(N-ethoxycarbonylcarbamoyl)penam.

To a stirred solution of 4.58 g. (10 mmole)6-(triphenylmethylamino)penicillanic acid and 1.45 ml. (10 mmole) oftriethylamine, in 75 ml. of acetonitrile, is added 1.15 g. (10 mmole) ofethoxycarbonyl isocyanate dissolved in 5 ml. of acetonitrile. Theresulting solution is stirred at ca. 25° C. for 16 hours, and then thesolvent is removed by evaporation in vacuo. The residue is re-dissolvedin chloroform, and the chloroform solution is washed successively withwater, sodium bicarbonate solution and sodium chloride solution. Thechloroform solution is then dried using anhydrous magnesium sulfate, andevaporated in vacuo. The residue is again re-dissolved in chloroform,and the chloroform solution is washed with dilute hydrochloric acid,dried using magnesium sulfate, and again evaporated in vacuo. Thisaffords the crude product, which is purified by chromatography usingsilica gel as the adsorbant and eluting the column with chloroformcontaining 4% by volume of ethanol. The final yield of6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[ethoxycarbonyl]carbamoyl)-penamis 2.54 g. (48% yield).

(B)6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[ethoxycarbonyl]tetrazol-5-yl)penam

To a stirred solution of 529 mg. (1 mmole) of6-triphenylmethylamino)-2,2-dimethyl-3-(N-[ethoxycarbonyl]carbamoyl)penamand 240 mg. (3 mmole) of pyridine, in 25 ml. of methylene chloride, isadded 208 mg. (1 mmole) of phosphorus pentachloride, at 0° C. Thereaction mixture is stirred at 0° C. for 0.5 hour and then at ca. 25° C.for 2 hours. The solvents and the excess pyridine are then removed byevaporation in vacuo, and the residue is re-dissolved in 15 ml. ofchloroform. The latter chloroform solution is cooled to 0° C., and 0.47g. (3 mmole) of tetramethylguanidinium azide is added in several smallportions with stirring. Stirring is continued for 2 hours at ambienttemperature, and then to the reaction mixture is added a further 15 ml.of chloroform followed by 30 ml. of water. The pH is adjusted to 6.5,and then the chloroform layer is removed. The chloroform solution iswashed with water followed by brine, and then it is dried usinganhydrous sodium sulfate. Removal of the solvent by evaporation in vacuoaffords crude6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[ethoxycarbonyl]tetrazol-5-yl)penam.The crude product is purified further by chromatography using silicagel.

EXAMPLE XXIX

Starting with 6-(triphenylmethylamino)penicillanic acid, or theappropriately-substituted 6-(triphenylmethylamino)penicillanic acid, andthe requisite isocyanate of formula R¹⁴ O--C(═O)--N═C═O, and followingthe procedure of Example XXVIII, the following compounds are prepared:

    __________________________________________________________________________     ##STR29##                                                                    R.sup.22 R.sup.23                                                                           R.sup.24                                                                            R.sup.14                                                  __________________________________________________________________________    H        H    H     CH.sub.3                                                  H        H    H     CH.sub.3 CH.sub.2 CH.sub.2                                H        H    H     (CH.sub.3).sub.2 CHCH.sub.2                               H        H    H     CH.sub.3 (CH.sub.2).sub.4 CH.sub.2                        H        H    H     C.sub.6 H.sub.5 CH.sub.2                                  H        H    H     4-O.sub.2 NC.sub.6 H.sub.4                                H        H    H     2-FC.sub.6 H.sub.4                                        H        H    H     3-BrC.sub.6 H.sub.4                                       H        H    H     C.sub.6 H.sub.5                                           H        H    H     4-(CH.sub.3 [CH.sub.2 ].sub.2 CH.sub.2 )C.sub.6                               H.sub.4                                                   H        H    H     3-CH.sub.3 OC.sub.6 H.sub.4                               H        H    H     4-([CH.sub.3 ].sub.2 CHO)C.sub.6 H.sub.4                  H        H    H     2,4-Cl.sub.2 C.sub.6 H.sub.3                              H        H    H     3,4-(CH.sub.3 CH.sub.2 O).sub.2 C.sub.6 H.sub.3           H        H    H     3,5-(CH.sub.3).sub.2 C.sub.6 H.sub.3                      H        H    H     4-Cl-3-CH.sub.3 C.sub.6 H.sub.3                           3-CH.sub.3                                                                             H    H     4-(CH.sub.3 CH.sub.2 CH.sub.2 O)-2-O.sub.2 NC.sub.6                           H.sub.3                                                   4-CH.sub.3 CH.sub.2 CH.sub.2                                                           H    H     4-(CH.sub.3 [CH.sub.2 ].sub.2 CH.sub.2 O)C.sub.6                              H.sub.4                                                   4-Br     H    H     CH.sub.3 CH.sub.2                                         2-F      H    H     C.sub.6 H.sub.5 CH.sub.2                                  3-C.sub.6 H.sub.5                                                                      H    H     C.sub.6 H.sub.5                                           3-CH.sub.3 CH.sub.2 O                                                                  H    H     4-O.sub.2 NC.sub.6 H.sub.4                                4-Cl     4-Cl H     2,4-(O.sub.2 N).sub.2 C.sub.6 H.sub.3                     4-CH.sub.3                                                                             3-CH.sub.3 O                                                                       3-CH.sub.3 O                                                                        CH.sub.3 CH.sub.2                                         4-CH.sub.3                                                                             4-CH.sub.3                                                                         4-CH.sub.3                                                                          C.sub.6 H.sub.5                                           __________________________________________________________________________

EXAMPLE XXX

Starting with 6-(triphenylmethylamino)penicillanic acid, or theappropriately-substituted 6-(triphenylmethylamino)penicillanic acid, andthe requisite isocyanate of formula R¹⁴ --SO₂ --N═C═O, and following theprocedure of Example XXVIII, the following compounds are prepared:

    ______________________________________                                         ##STR30##                                                                    R.sup.22 R.sup.23 R.sup.24 R.sup.14                                           ______________________________________                                        H        H        H        CH.sub.3                                           H        H        H        CH.sub.3 CH.sub.2                                  H        H        H        (CH.sub.3).sub.2 CHCH.sub.2                        H        H        H        C.sub.6 H.sub.5 CH.sub.2                           H        H        H        C.sub.6 H.sub.5                                    H        H        H        4-O.sub.2 NC.sub.6 H.sub.4                         H        H        H        3-FC.sub.6 H.sub.4                                 H        H        H        2-ClC.sub.6 H.sub.4                                H        H        H        4-BrC.sub.6 H.sub.4                                H        H        H        2-(CH.sub.3 CH.sub.2)C.sub.6 H.sub.4               H        H        H        3-(CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2)C.sub.6                                H.sub.4                                            H        H        H        4-CH.sub.3 OC.sub.6 H.sub.4                        H        H        H        3-([CH.sub.3 ].sub.2 CHCH.sub.2 O)C.sub.6                                     H.sub.4                                            H        H        H        2,4-Cl.sub.2 C.sub.6 H.sub.3                       H        H        H        3-CH.sub.3 -4-CH.sub.3 OC.sub.6 H.sub.3            H        H        H        2,4-(O.sub.2 N).sub.2 C.sub.6 H.sub.3              H        H        H        2-CH.sub.3 O-5-O.sub.2 NC.sub.6 H.sub.3            2-CH.sub.3                                                                             H        H        CH.sub.3                                           3-CH.sub.3 CH.sub.2                                                                    H        H        C.sub.6 H.sub.5 CH.sub.2                           3-Cl     H        H        4-O.sub.2 NC.sub.6 H.sub.4                         4-CH.sub.3 O                                                                           H        H        C.sub.6 H.sub.5                                    4-C.sub.6 H.sub.5                                                                      H        H        CH.sub.3 CH.sub.2                                  3-Cl     3-Cl     H        4-ClC.sub.6 H.sub.4                                3-CH.sub.3 O                                                                           3-CH.sub.3 O                                                                           3-CH.sub.3 O                                                                           2,4-(O.sub.2 N).sub.2 C.sub.6 H.sub.3              ______________________________________                                    

Example XXXI 6-(Triphenylmethylamino)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred mixture of 2 ml. of tetrahydrofuran and 4 ml. of water isadded 150 mg. of6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[ethoxycarbonyl]tetrazol-5-yl)penam.The pH of the mixture is adjusted to 9.5, and stirring is continued atthat pH for a further 30 minutes, at ambient temperature. The bulk ofthe tetrahydrofuran is removed by evaporation in vacuo, and the residueis portioned between water and ethyl acetate at pH 9. The ethyl acetateis removed and discarded. Fresh ethyl acetate is added and the pH isadjusted to 2.0. The ethyl acetate layer is removed, washed with water,dried using anhydrous sodium sulfate, and evaporated in vacuo to givethe crude title compound.

EXAMPLE XXXII

Reaction of any of the6-(triphenylmethylamino)-2,2-dimethyl-3-(1-substitutedtetrazol-5-yl)penam or 6-(substitutedtriphenylmethylamino)-2,2-dimethyl-3-(1-substituted tetrazol-5-yl)penamcompounds, listed in Examples XXIX and XXX, with water at pH 9.5,according to the procedure of Example XXXI, results in removal of theC(═O)--O--R¹⁴ or SO₂ --R¹⁴ group and its replacement by hydrogen. Inthis way, the following compounds are obtained:

    ______________________________________                                         ##STR31##                                                                    R.sup.22      R.sup.23      R.sup.24                                          ______________________________________                                        H             H             H                                                 3-CH.sub.3    H             H                                                 4-CH.sub.3 CH.sub.2 CH.sub.2                                                                H             H                                                 4-Br          H             H                                                 2-F           H             H                                                 3-C.sub.6 H.sub.5                                                                           H             H                                                 3-CH.sub.3 CH.sub.2 O                                                                       H             H                                                 4-Cl          4-Cl          H                                                 4-CH.sub.3    3-CH.sub.3 O  3-CH.sub.3 O                                      4-CH.sub.3    4-CH.sub.3    4-CH.sub.3                                        2-CH.sub.3    H             H                                                 3-CH.sub.3 CH.sub.2                                                                         H             H                                                 3-Cl          H             H                                                 4-CH.sub.3 O  H             H                                                 4-C.sub.6 H.sub.5                                                                           H             H                                                 3-Cl          3-Cl          H                                                 3-CH.sub.3 O  3-CH.sub.3 O  3-CH.sub.3 O                                      ______________________________________                                    

EXAMPLE XXXIII 6-Amino-2,2-dimethyl-3-(5-tetrazolyl)penam

To a slurry of dry acetone (5 ml.) and6-triphenylmethylamino-2,2-dimethyl-3-(5-tetrazolyl)penam (483 mg., 1.0mmole) at room temperature is added p-toluenesulfonic acid monohydrate(209 mg., 1.1 mmole). The resulting solution is stirred for 10 minutes,and then ether (30 ml.) is added over a five minute period. The mixtureis stirred for ten minutes after which the solvent is decanted from theresidue. The residue is dissolved in tetrahydrofuran (30 ml.) and placedon a column (300×6 mm.) packed with 10 g. of Florisil (syntheticmagnesium silicate). The column is eluted with tetrahydrofuran until atotal of 125 ml. is collected. The eluate is concentrated to drynessunder reduced pressure at 40° C. to give 210 mg. of solid. The solid isslurried in ether (30 ml.), filtered, washed with ether and air-dried.Yield=121 mg. (50%). NMR (DMSO-d₆): 5.88 (s, 3H), 5.10 (s, 3H) 5.52 (d,1H), 4.60 (d, 2H), 1.59 (s, 3H) and 1.08 ppm (s, 3H).

EXAMPLE XXXIV

When each of the 6-(substitutedtriphenylmethylamino)-2,2-dimethyl-3-(5-tetrazolyl)penam compoundsdescribed in Example XXXII is reacted with p-toluenesulfonic acid,according to the procedure of Example XXXIII, the product in each caseis 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam.

EXAMPLE XXXV6-Amino-2,2-dimethyl-3-(1-[ethoxycarbonyl]tetrazol-5-yl)penam

To a stirred solution of 554 mg. of6-triphenylmethylamino)-2,2-dimethyl-3-(1-[ethoxycarbonyl]tetrazol-5-yl)penamin 2 ml. of acetone is added a solution of 190 mg. of p-toluenesulfonicacid of 1 ml. of acetone. Stirring is continued for a further 3 hours,and then the acetone is removed by evaporation in vacuo. The residue isslurried in ether, filtered and dried, to give the title compound as itsp-toluenesulfonate salt.

The above p-toluenesulfonate salt is added to a mixture of 15 ml. ofwater and 15 ml. of chloroform. The pH of the aqueous phase is adjustedto 7.0, and the chloroform layer is removed. The chloroform is driedusing sodium sulfate, and then it is evaporated in vacuo to give thetitle compound as its free base.

EXAMPLE XXXVI

Reaction of the appropriate6-(triphenylmethylamino)-2,2-dimethyl-3-(1-substitutedtetrazol-5-yl)penam or 6-(substitutedtriphenylmethylamino)-2,2-dimethyl-3-(1-substituted tetrazol-5-yl)penam,chosen from those in Examples XXIX and XXX, with p-toluenesulfonic acid,according to the procedure of Example XXXV, provides the followingcompounds as their p-toluenesulfonate salts.

    ______________________________________                                         ##STR32##                                                                        R.sup.2                                                                   ______________________________________                                        CO.sub.2 CH.sub.3                                                             CO.sub.2 (CH.sub.2 CH.sub.2 CH.sub.3)                                         CO.sub.2 (CH.sub.2 CH[CH.sub.3 ].sub.2)                                       CO.sub.2 CH.sub.2 C.sub.6 H.sub.5                                             CO.sub.2 (4-C.sub.6 H.sub.4 NO.sub.2)                                         CO.sub.2 (2-C.sub.6 H.sub.4 F)                                                CO.sub.2 (3-C.sub.6 H.sub.4 Br)                                               CO.sub.2 C.sub.6 H.sub.5                                                      CO.sub.2 (4-C.sub.6 H.sub.4 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3)              CO.sub.2 (3-C.sub.6 H.sub.4 CH.sub.3)                                         CO.sub.2 (4-C.sub.6 H.sub.4 OCH[CH.sub.3 ].sub.2)                             CO.sub.2 (2,4-C.sub.6 H.sub.3 Cl.sub.2)                                       CO.sub.2 (3,4-C.sub.6 H.sub.3 [OCH.sub.2 CH.sub.3 ].sub.2)                    CO.sub.2 (3,5-C.sub.6 H.sub.3 [CH.sub.3 ].sub.2)                              CO.sub.2 (C.sub.6 H.sub.3 -4-Cl-3-CH.sub.3)                                   CO.sub.2 (C.sub.6 H.sub.3 -4-[OCH.sub.2 CH.sub.2 CH.sub.3 ]-2-NO.sub.2)       CO.sub.2 (4-C.sub.6 H.sub.4 OCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3)             CO.sub.2 (2,4-C.sub.6 H.sub.3 [NO.sub.2 ].sub.2)                              SO.sub.2 CH.sub.3                                                             SO.sub.2 CH.sub.2 CH.sub.3                                                    SO.sub.2 (CH.sub.2 CH[CH.sub.3 ].sub.2)                                       SO.sub.2 CH.sub.2 C.sub.6 H.sub.5                                             SO.sub.2 C.sub.6 H.sub.5                                                      SO.sub.2 (4-C.sub.6 H.sub.4 NO.sub.2)                                         SO.sub.2 (3-C.sub.6 H.sub.4 F)                                                SO.sub.2 (2-C.sub.6 H.sub.4 Cl)                                               SO.sub.2 (4-C.sub.6 H.sub.4 Br)                                               SO.sub.2 (2-C.sub.6 H.sub.4 CH.sub.2 CH.sub.3)                                SO.sub.2 (3-C.sub.6 H.sub.4 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3)              SO.sub.2 (4-C.sub.6 H.sub.4 OCH.sub.3)                                        SO.sub.2 (3-C.sub.6 H.sub.4 OCH.sub.2 CH[CH.sub.3 ].sub.2)                    SO.sub.2 (2,4-C.sub.6 H.sub.3 Cl.sub.2)                                       SO.sub.2 (C.sub.6 H.sub.3 -3-CH.sub.3 -4-OCH.sub.3)                           SO.sub.2 (2,4-C.sub.6 H.sub.3 [NO.sub.2 ].sub.2)                              SO.sub.2 (C.sub.6 H.sub.3 -2-OCH.sub. 3 -2-NO.sub.2)                          ______________________________________                                    

EXAMPLE XXXVII6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[2-methoxycarbonylethyl]tetrazol-5-yl)penamA.6-(Triphenylmethylamino)-2,2-dimethyl-3-(N-[2-methoxycarbonylethyl]carbamoyl)penam

To a stirred solution of 35 g. of 6-(triphenylmethylamino)penicillanicacid in 250 ml. of dry, ethanol-free chloroform, is added 11.7 ml. oftriethylamine at 0°-3° C. The solution thus obtained is then addeddropwise, with stirring, at 0°-6° C., to a second solution, preparedfrom 7.3 ml. of ethyl chloroformate in 155 ml. of dry, ethanol-freechloroform. Stirring is continued for a further 10 minutes. This affordsa chloroform solution of the mixed anhydride of6-(triphenylmethylamino)penicillanic acid.

In a separate flask, a solution of β-alanine methyl ester is prepared byadding 11.7 ml. of triethylamine to a slurry of 10.73 g. of β-alaninemethyl ester hydrochloride and 2 g. of anhydrous sodium sulfate in 115ml. of dry, ethanol-free chloroform, at ca. 10° C. Stirring is continuedfor a further 10 minutes.

The latter amino-ester solution is then added dropwise, with stirring at3°-6° C., to the above-described mixed anhydride solution. After the endof the addition, stirring is continued for a further 2 hours.

At this point, the reaction solution is washed successively with threeportions of water ane one portion of brine. The solution is then driedusing anhydrous sodium sulfate, and evaporated in vacuo to give 40.1 g.of crude6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[2-methoxycarbonylethyl]carbamoyl)penamas a glassy solid, m.p. 60°-70° C. The crude product is purified byextracting it into refluxing ether, treating the filtered solution withactivated carbon, and then re-precipitating the product by the additionof petroleum ether.

B.6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[2-methoxycarbonylethyl]tetrazol-5-yl)penam

To a stirred solution of 2 g. of the amide described under A above, in 5ml. of dry, ethanol-free chloroform, is added, at ca. 0° C., 1.36 ml. ofpyridine, followed by a solution of 620 mg. of phosgene in 4 ml. of dry,ethanol-free chloroform. The solution is stirred for 2.5 hours, atambient temperature, and then the solvent is removed by evaporation invacuo. The residue is re-dissolved in 9 ml. of dry, ethanol-freechloroform, and 580 mg. of tetramethylguanidinium azide is added. Thereaction mixture is stirred for 45 minutes, at which point a further 200mg. of tetramethylguanidinium azide is added. The reaction mixture isthen stirred 18 hours to complete the conversion to tetrazole. To thereaction solution is then added saturated sodium bicarbonate solution,in sufficient quantity that the pH of the aqueous phase is 7.6. Thechloroform layer is removed, washed with water at pH 5, washed withwater at pH 7, dried using anhydrous sodium sulfate, and finallyevaporated in vacuo. This affords 2.19 g. of crude product, which isrecrystallized from methanol giving 1.11 g (48% yield) of product withm.p. 100°-105° C. The NMR spectrum (CDCl₃) shows absorptions at 7.40 ppm(m, 15H), 5.15 ppm (s, 1H), 3.80 (m, 4H), 3.70 ppm (s, 3H), 3.10 ppm (t,2H), 1.70 ppm (s, 3H) and 1.17 ppm (s, 3H), and further indicates thatthe product contains methanol of solvation.

EXAMPLE XXXVIII

The procedure of Example XXXVII is repeated, except that where necessarythe 6-(triphenylmethylamino)penicillanic acid is replaced by theappropriately-substituted 6(triphenylmethylamino)penicillanic acid, andwhere necessary the β-alanine methyl ester is replaced by theappropriate amine to produce the following compounds

    ______________________________________                                         ##STR33##                                                                    R.sup.22                                                                              R.sup.23 R.sup.24 Y                                                   ______________________________________                                        H       H        H        C(=O)OCH.sub.2 CH.sub.3                             H       H        H        C(=O)OCH(CH.sub.3).sub.2                            H       H        H        C(=O)OCH.sub.2 (CH.sub.2).sub.4 CH.sub.3            H       H        H        C(=O)OC.sub.6 H.sub.5                               H       H        H        SO.sub.2 CH.sub.3                                   H       H        H        SO.sub.2 CH.sub.2 (CH.sub.2).sub.2 CH.sub.3         H       H        H        SO.sub.2 NHC.sub.6 H.sub.5                          H       H        H        SO.sub.2 N(C.sub.6 H.sub.5).sub.2                   H       H        H        SO.sub.2 N(CH.sub.3)C.sub.6 H.sub.5                 H       H        H        SO.sub.2 OCH.sub.3                                  H       H        H        SO.sub.2 OCH.sub.2 CH.sub.3                         H       H        H        SO.sub.2 OCH.sub.2 CH(CH.sub.3).sub.2               H       H        H        SO.sub.2 C.sub.6 H.sub.5                            H       H        H        SO.sub.2 NH.sub.2                                   H       H        H        SO.sub.2 NHCH.sub.3                                 H       H        H        SO.sub.2 N(CH.sub.2 CH.sub.2 CH.sub.3).sub.2        H       H        H        SO.sub.2 NHCH.sub.2 C.sub.6 H.sub.5                 H       H        H        CN                                                  2-F     H        H        C(=O)OCH.sub.3                                      3-CH.sub.3 O                                                                          H        H        SO.sub.2 CH.sub.2 CH.sub.3                          3-C.sub.6 H.sub.5                                                                     H        H        SO.sub.2 NH(CH.sub.2 [CH.sub.2 ].sub.2 CH.sub.3)                              6                                                   3-Cl    3-Cl     H        C(=O)OCH.sub.3                                      4-CH.sub.3                                                                            4-CH.sub.3                                                                             4-CH.sub.3                                                                             C(=O)OCH.sub.2 CH.sub.3                             ______________________________________                                    

EXAMPLE XXXIX6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[2-methoxycarbonylethyl]tetrazol-5-yl)penam

To a stirred solution of 8 g. of6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[2-methoxycarbonylethyl]carbamoyl)penam(prepared as described in Example XXXVII, Part A) in 20 ml. of dry,ethanol-free chloroform, is added 5.4 ml. of pyridine. To this solutionis then added a solution of 2.7 g. of phosgene in 16 ml. of dry,ethanol-free chloroform, at ca. 0° C. The reaction mixture is stirred atambient temperature for 1.5 hours, and then the solvent is removed byevaporation in vacuo. The viscous residue is re-dissolved in 36 ml. ofdry chloroform, the solution is cooled to ca 0° C., and 2.6 ml. oftrimethylsilyl azide is added. The reaction mixture is stirred atambient temperature for 17 hours. At this point 1.26 g. of solid sodiumbicarbonate is added to the chloroform solution, followed by sufficientaqueous saturated sodium bicarbonate to give a pH of 7.6. The chloroformis separated, washed with water, washed with brine, dried usinganhydrous sodium sulfate, treated with 200 mg. of activated carbon, andfinally evaporated in vacuo. The residue is triturated with cyclohexane,and then recrystallized from methanol, giving 3.85 g. (46% yield) of thetitle compound, m.p. 94°-98° C. After further recrystallization of theproduct from methanol, the melting point is raised to 104°-106° C. TheNMR spectrum (CDCl₃) shows absorptions at 7.40 ppm (m, 15H), 5.15 ppm(s, 1H), 3.80 ppm (m, 4H), 3.70 ppm (s, 3H), 3.10 ppm (t, 2H), 1.70 ppm(s, 3H) and 1.17 ppm (s, 3H), and further indicates that the productcontains ca. 3% of methanol of solvation.

EXAMPLE XL 6-(Triphenylmethylamino)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 600 mg. of6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[2-methoxycarbonylethyl]tetrazol-5-yl)penam(containing ca 4.5% of methanol) in 1 ml. of chloroform, is added asolution of 375.2 mg. of diazabicyclo[4.3.0]non-5-ene in 0.5 ml. ofchloroform. Stirring is continued for a further 3 hours, and then thesolution is diluted with a further 2 ml. of chloroform. The lattersolution is washed quickly with 5 ml. of 2 N hydrochloric acid, and thena further 5 ml. of 2 N hydrochloric are added. The resulting mixture iscooled to ca 0° C., and the solid which precipitates is filtered off,giving 323 mg. (71% yield) of the title compound. The NMR spectrum(DMSO-d₆) of the product shows absorptions at 7.40 ppm (m, 15H), 5.30ppm (s, 1H), 4.60 ppm (m, 2H), 1.58 ppm (s, 3H) and 0.78 ppm (s, 3H).

EXAMPLE XLI

Reaction of any of the6-(triphenylmethylamino)-2,2-dimethyl-3-(1-substitutedtetrazol-5-yl)penam or 6-(substitutedtriphenylmethylamino)-2,2-dimethyl-3-(1-substituted tetrazol-5-yl)penamcompounds, listed in Example XXXVIII, with diazabicyclo[4.3.0]non-5-ene,according to the procedure of Example XL, results in removal of the2-substituted ethyl substituent from the tetrazole ring, and itsreplacement by hydrogen. In this way, the following compounds areobtained:

    ______________________________________                                         ##STR34##                                                                    R.sup.22       R.sup.23     R.sup.24                                          ______________________________________                                        H              H            H                                                 2-F            H            H                                                 3-CH.sub.3 O   H            H                                                 3-C.sub.6 H.sub.5                                                                            H            H                                                 3-Cl           3-Cl         H                                                 4-CH.sub.3     4-CH.sub.3   4-CH.sub.3                                        ______________________________________                                    

The above 6-(substitutedtriphenylmethylamino)-2,2-dimethyl-3-(5-tetrazolyl)penam compounds areconverted into 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam by reactionwith p-toluenesulfonic acid, according to the procedure of ExampleXXXIII.

EXAMPLE XLII 6-(2-Phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

A flask containing 965 mg. of6-amino-2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-5-yl)penamp-toluenesulfonate, 40 drops of anisole, and 5 ml. of trifluoroaceticacid is immersed in a water-bath maintained at 35°-40° C. The progressof the reaction is followed by removing samples at intervals, andrecording their nuclear magnetic resonance spectra. After about 25minutes, the removal of the 4-methoxybenzyl group is found to beapproximately 90% complete. At this point the reaction solution is addedto a rapidly-stirred, ice-cold solution of 10 ml. of pyridine in 50 ml.of chloroform. Stirring is continued for 5 minutes, and then 0.24 ml. ofphenylacetyl chloride is added. The cooling bath is removed and thereaction mixture is stirred for a further 20 minutes. A 100-ml. portionof water is added, and the pH of the aqueous phase is then adjusted to2.5 by the dropwise addition of 0.5 N hydrochloric acid. The chloroformlayer is separated off, washed with saturated brine, dried usinganhydrous sodium sulfate and then it is evaporated to dryness in vacuo.The crude product thus obtained is re-dissolved in chloroform, and thesolution is divided into two equal portions. To one of these portions isadded an equal volume of water. The layers are stirred vigorously andthe pH of the aqueous phase is raised to 6.9 by the dropwise addition of0.1 N sodium hydroxide solution. The chloroform is separated off anddiscarded, and then an equal quantity of fresh chloroform is added tothe aqueous phase. The layers are stirred vigorously and the pH isadjusted to 2.5 using dilute hydrochloric acid. The chloroform isseparated off, washed with saturated brine, dried using anhydrousmagnesium sulfate and then evaporated to dryness in vacuo.

This affords 197 mg. of an oily residue. The residue is re-dissolved in3 ml. of chloroform which is then added dropwise to 30 ml. of hexane.The fluffy white solid which precipitates is filtered off, giving 80 mg.of 6-(2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. IR(KBrdisc): 1795, 1660 and 1510 cm⁻¹. NMR (in CDCl₃): 7.20 (broad s,5H), 5.55(m,2H), 5.15 (s,1H), 3.60 (broad s,2H), 1.40 (s,3H) and 1.05 ppm (s,3H).

EXAMPLE XLIII 6-(2-Phenylacetamido)-2,2-Dimethyl-3-(5-Tetrazolyl)Penam

A mixture of p-toluenesulfonic acid monohydrate (788 mg., 4.14 mmoles),acetone (35 ml.) and6-triphenylmethylamino-2,2-dimethyl-3-(5-tetrazolyl)penam (2.0 g., 4.14mmole) is stirred for twenty minutes at room temperature and is thendiluted with water (100 ml.) and isopropylether (100 ml.). The biphasicmixture is stirred vigorously and adjusted to pH 7 with 2 N sodiumhydroxide. Phenylacetyl chloride (700 mg., 4.55 mmole freshly distilled)is added and the reaction mixture maintained at pH 5.5-6.5 by additionof 2 N sodium hydroxide as necessary. Reaction is continued until the pHlevels off at 6.5. The two phases are separated and the aqueous phase iswashed with ether (2×50 ml.). Chloroform (100 ml.) is added and the pHis adjusted to 2 by addition of 6 N HCl. The mixture is stirred, thephases separated and the aqueous phase extracted with chloroform (2×50ml.). The chloroform phases are combined, dried (Na₂ SO.sub. 4), andthen concentrated under reduced pressure to about 50 ml. volume. A 1:1solution of ether-hexane is added dropwise with vigorous stirring untilprecipitation of the product is complete. The white precipitate isfiltered and air-dried. The yield is 850 mg. (57.4%), m.p. 168°-170°.NMR (DMSO-d₆): 7.30 (s, 5H), 5.80-5.42 (m, 2H), 5.28 (s, 1H), 3.60 (s,2H), 1.68 (s, 3H) and 1.10 ppm (s, 3H).

EXAMPLE XLIV6-(3-[2-Chlorophenyl]-5-methyl-4-isoxazolecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

A stirred slurry of 240 mg. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)-penam in 10 ml. of water is cooledto 0° C., and then the pH is adjusted to 7.1 using 1 N sodium hydroxide.The resultant solution is diluted with 10 ml. of acetone, and then asolution of 281 mg. of 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonylchloride (Doyle, et al., Journal of the Chemical Society [London], 5838[1963]) in 10 ml. of dry acetone is added portionwise during 3-4minutes. During the addition the pH of the solution is maintained in therange from 5.5 to 6.5 by adding 0.1 N sodium hydroxide. At the end ofthe addition the reaction is stirred an additional 15 minutes at about0° C. At this point, the acetone is removed by evaporation under reducedpressure at about 15° C., the resultand aqueous phase is filtered andthe pH is lowered to 2 with dilute hydrochloric acid. The product isextracted into chloroform. The extract is dried using anhydrous sodiumsulfate, and then it is evaporated in vacuo to give the crude product asa gum. The gum is re-dissolved in 3 ml. of tetrahydrofuran, and then thesolution is added to 15 ml. of water at 10° C. The pH of the solution israised to 7.0 by the addition of 0.1 N sodium hydroxide, the solution isfiltered, and then it is lyophilized. This affords 430 mg. of the sodiumsalt of6-(3-[2-chlorophenyl]-5-methyl-4-isoxazolecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl)penamas an amorphous solid. The infrared spectrum (KBr disc) of the productshows absorption bands at 1770 cm⁻¹ (β-lactam carbonyl), 1650 cm⁻¹(amide I band) and 1520 cm⁻¹ (amide II band). The NMR spectrum (inCDCl₃) shows absorption bands at 7.40 ppm (multiplet, aromatichydrogens), 5.90 and 5.60 (2 doublets, C-5 and C-6 hydrogens), 5.15 ppm(singlet, C-3 hydrogen), 2.80 ppm (singlet, isoxazole methyl hydrogens),1.50 ppm (singlet, C-2 methyl hydrogens) and 1.05 ppm (singlet, C-2methyl hydrogens).

EXAMPLE XLV

When the procedure of Example XLIV is repeated, and the3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl chloride used therein isreplaced by 3-phenyl-5-methylisoxazole-4-carbonyl chloride,3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonyl chloride and3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride,respectively, there is produced:

6-(3-phenyl-5-methyl-4-isoxazolecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(3-[2,6-dichlorophenyl]-5-methyl-4-isoxazolecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,and

6-(3-[2-chloro-6-fluorophenyl]-5-methyl-4-isoxazole-carboxamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

respectively.

The starting acid chlorides used in this experiment are prepared by theaction of thionyl chloride on the corresponding acids, which in turn areprepared by the published methods (Long, et al., Journal of the ChemicalSociety [London], 5838 [1963]; U.S. Pat. No. 2,996,501).

EXAMPLE XLVI6-(2-Azido-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

A solution of 1.61 grams (9.1 mmole) of 2-azido-2-phenylacetic acid[Forster and Mueller, J. Chem. Soc., 97, 138 (1910)] and 5 ml. ofthionyl chloride is heated under reflux for hour. The reaction solutionis evaporated under reduced pressure to furnish a residue of2-azido-2-phenylacetyl chloride which is dissolved in 10 ml. ofdichloromethane and is added over 5 minutes to a stirred ice-bath cooledsolution of 2.4 grams (10 mmole) of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 2.02 grams (20 mmole) oftriethylamine and 50 ml. of dichloromethane. After 30 minutes thereaction solution is allowed to warm to room temperature. After afurther 3 hours, the more volatile components of the solution areevaporated under reduced pressure and the residue is taken up in 50 ml.of water. The aqueous solution is washed twice with 25 ml. portions ofethyl acetate, and it is then adjusted to pH 2.5 by the careful additionof 6 N hydrochloric acid. The resulting cloudy mixture is extractedtwice with 30 ml. portions of ethyl acetate. After being dried usinganhydrous sodium sulfate, the combined extracts are filtered and thesolvent is evaporated in vacuo. The residue is dissolved in 10 ml. ofdichloromethane; 1.0 ml. of triethylamine is added, and the resultingsolution is poured into 350 ml. of rapidly stirred diethyl ether. Thesolid which precipitates is filtered off giving 1.62 g. (38% yield) ofthe title compound as its triethylamine salt. IR (KBr disc): 1792 cm⁻¹(β-lactam) and 1693 cm⁻¹ (amide I). NMR (in D₂ O/NaHCO₃): 7.40 ppm(s,5H, aromatic hydrogens), 5.60 and 5.80 ppm (m and m, 2H, C-5 and C-6hydrogens), 5.30 ppm (m,2H, C-3 hydrogen and side-chain methinehydrogen), 3.20 (q,6H, NCH₂ CH₃), 1.60 ppm (s,3H, C-2 methyl hydrogens),1.30 ppm (t,9H, NCH₂ CH₃), 1.10 ppm (s,3H, C-2 methyl hydrogens).

EXAMPLE XLVII 6-(2-Cyanoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a solution of 2.0 g. of 2-cyanoacetic acid and 2.7 g. ofN-hydroxysuccinimide, in 50 ml. of tetrahydrofuran, is added 4.85 g. ofdicyclohexylcarbodiimide. The mixture is stirred at ambient temperatureovernight, and then the precipitate is filtered off and discarded.Evaporation of the solvent then affords the N-hydroxysuccinimide esterof cyanoacetic acid, which after recrystallization from chloroform hasm.p. 123°-30° C. and is suitable for use as described below. (A morehighly purified sample has m.p. 128°-130° C.)

To a stirred suspension of 177 mg. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 10 ml. of methylenechloride, under nitrogen, is added 157 mg. of triethylamine. Stirring iscontinued until a clear solution is obtained (ca. 35 minutes). To thissolution is then added 135 mg. of the N-hydroxysuccinimide ester ofcyanoacetic acid, all in one portion. After stirring for a further 2.5hours, the reaction mixture is poured into 15 ml. of water, and the pHof the aqueous phase is adjusted to 8.0. The methylene chloride layer isseparated off and discarded. The aqueous phase is acidified to pH 2, andthen extracted with ethyl acetate. The ethyl acetate is dried usinganhydrous sodium sulfate, and then to it is added a solution of 110 mg.of sodium 2-ethylhexanoate in a small volume of ethyl acetate. Theprecipitate which forms is filtered off, to give 138 mg. (57% yield) ofthe sodium salt of6-(2-cyanoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infraredspectrum (KBr disc) of the product shows absorption bands at 2260 cm⁻¹(cyano), 1775 cm⁻¹ (β-lactam carbonyl), 1680 cm⁻¹ (amide I band) and1550 cm⁻¹ (amide II band). The NMR spectrum (in D₂ O) shows absorptionsat 5.90 and 5.40 ppm (2 doublets, C-5 and C-6 hydrogens), 5.30 ppm(singlet, C-3 hydrogen) 1.65 ppm (singlet, C-2 methyl hydrogens) and1.00 ppm (singlet, C-2 methyl hydrogens).

EXAMPLE XLVIII6-(2-[1-Tetrazolyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 90 mg. of tetrazole-1-acetic acid and 71 mg. oftriethylamine, in 5 ml. of chloroform, cooled to 0° C., is added 85 mg.of pivaloyl chloride. Stirring is continued at 0° C. for a further 30minutes, and then the resultant solution is added to an ice-coldsolution prepared from 169 mg. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 142 mg. of triethylamine and5 ml. of chloroform. This combined solution is stirred at about 0° C.for 2.5 hours. It is then warmed to ambient temperature and poured into20 ml. of water. The pH of the aqueous phase is raised to 7.0, thelayers are separated, and the chloroform is discarded. The aqueous phaseis acidified to pH 2, and then it is extracted with ethyl acetate. Theethyl acetate is dried, and then to it is added a solution of 100 mg. ofsodium 2-ethylhexanoate in a small volume of ethyl acetate. The solidwhich precipitates is filtered off, giving 80 mg. (31% yield) of thesodium salt of6-(2-[1-tetrazolyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. Theinfrared spectrum of the product (KBr disc) shows absorption bands at1785 cm⁻¹ (β-lactam carbonyl), 1695 cm⁻¹ (amide I band) and 1575 cm⁻¹(amide II band). The NMR spectrum (in D₂ O) shows absorption bands at5.90-5.40 ppm (multiplet, C-5 and C-6 hydrogens), 5.25 ppm (broadsinglet, tetrazole hydrogen), 5.20 ppm (singlet, C-3 hydrogen), 1.70 ppm(singlet, C-2 methyl hydrogens) and 1.00 ppm (singlet, C-2 methylhydrogens).

The tetrazole-1-acetic acid used in this Example is obtained by themethod described in U.S. Pat. No. 3,468,874.

EXAMPLE XLIX

Using the procedure of Example XLVIII, and replacing thetetrazole-1-acetic acid by the appropriate acid, the following compoundsare prepared as their sodium salts.

6-(2-[2-tetrazolyl]acetamido)-2,2-dimethyl-3(5-tetrazolyl)penam,

6-(D-2-hydroxy-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-hydroxy-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-hydroxy-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-hydroxy-2-[2-furyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-hydroxy-2-[2-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[2-(hydroxymethyl)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamand

6-(2-[4-(hydroxymethyl)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazol-5-yl)penam,

respectively.

The tetrazole-2-acetic acid is prepared by the method described in U.S.Pat. No. 3,468,874. D-2-Hydroxy-2-phenylacetic acid is commerciallyavailable. D-2-Hydroxy-2-(p-hydroxyphenyl)acetic acid,D-2-hydroxy-2-(m-chlorophenyl)acetic acid, D-2-hydroxy-2-(2-furyl)aceticacid and D-2-hydroxy-2(2-thienyl)acetic acid are each prepared from thecorresponding aldehyde, using the method of Corson et al., OrganicSynthesis, Collective Volume I, p. 336.

EXAMPLE L 6-(2-Phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

A stirred slurry of 480 mg. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 10 ml. of water is cooledto 0° C., and then the pH is adjus using 1 N sodium hydroxide. To thissolution is then added 0.25 ml. of phenoxyacetyl chloride, in portions,with the pH of the solution being maintained between 7 and 8 during theaddition, using 0.1 N sodium hydroxide. The solution is stirred afurther 30 minutes at 0° C. at pH 8. It is then extracted withchloroform, and the extracts are discarded. The aqueous phase isacidified to pH 2 with dilute hydrochloric acid, and then it is furtherextracted with chloroform. The latter extracts are dried using calciumsulfate and then evaporated in vacuo to give the crude product as agummy solid. This is purified by dissolving it in 20 ml. of chloroform,and adding the resultant solution dropwise to 250 ml. of hexane. Theprecipitate which forms is filtered off, giving 385 mg. of6-(2-phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as a whiteamorphous solid. The infrared spectrum (KBr disc) of the product showsabsorption bands at 1785 cm⁻¹ (β-lactam carbonyl), 1670 cm⁻¹ (amide Iband) and 1540 cm⁻¹ (amide II band). The NMR spectrum (in DMSO-d₆) showsabsorption bands at 7.50-6.70 ppm (multiplet, aromatic hydrogens), 5.70ppm (multiplet, C-5 and C-6 hydrogens), 5.35 ppm (singlet, C-3hydrogen), 4.60 ppm (singlet, methylene hydrogens), 1.60 ppm (singlet,C-2 methyl hydrogens), and 1.05 ppm (singlet, C-2 methyl hydrogens).

EXAMPLE LI

The procedure of Example L is repeated, using the appropriate acidchloride, to provide the following compounds

    __________________________________________________________________________     ##STR35##                                                                                  Melting                                                                            Infrared                                                             Yield                                                                             Point                                                                              Spectrum                                                    R.sup.1  (%) (°C.)                                                                       (cm.sup.-1)                                                                         NMR Spectrum (ppm)                                   __________________________________________________________________________    2-(2-thienyl)acetyl                                                                     26  192-194                                                                            1808, 1718,                                                                         7.10(m,1H), 7.00(m,2H), 5.70(m,2H), 5.30(s,1H),                               3.90                                                                    1678  (s,2H), 1.70(s,3H), 1.10(s,3H) . DMSO-d.sub.6.       phenoxycarbonyl                                                                         43  102-118                                                                            1795, 1740                                                                          9.00(s,1H), 7.40-7.70(m,5H), 6.20(d,1H),                                      5.70(m,2H),                                                                   5.35(s,1H), 1.90(s,3H), 1.13(s,3H) .                                          CDCl-d.sub.3.                                        benzyloxycarbonyl                                                                       30  145-170                                                                            1800, 1725                                                                          11.30(s,1H), 7.40(s,5H), 5.70(m,2H), 5.30(s,1H),                              5.15                                                                          (s,2H), 1.70(s,3H), 1.10(s,3H) . CDCl.sub.3.         ethoxycarbonyl                                                                          32   80-115                                                                            1800, 1725                                                                          10.70(s,1H), 5.75(m,2H), 5.16(s,1H), 4.20(q,2H),                              1.75                                                                          (s,3H), 1.50-1.10(m,6H) . CDCl.sub.3.                __________________________________________________________________________

EXAMPLE LII 6-(Acetamido-2,2-dimethyl-3-(5-tetrazolyl)penam

The procedure of Example L is repeated, except that the phenoxyacetylchloride used therein is replaced by acetic anhydride. This affords a48% yield of the title compound. IR (KBr disc): 1780 cm⁻¹ (β-lactam),1645 cm⁻¹ (amide I). NMR (in DMSO-d₆): 5.65 ppm (m, 2H), 5.25 ppm (s,1H), 1.95 ppm (s, 3H), 1.70 ppm (s, 3H), and 1.10 ppm (s, 3H).

EXAMPLE LIII

Reaction of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam with theappropriate acid chloride, according to the procedure of Example Lprovides the following compounds:

6-(2[cyclopent-2-enyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[cyclohex-2-enyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[cyclohept-1-enyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[cyclooct-1-enyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and,

6-(2-[cyclohept-2,4,6-trienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

respectively.

EXAMPLE LIV

The procedure of Example L is repeated, except that the phenoxyacetylchloride used therein is replaced by an equimolar amount of theappropriate acid chloride, to produce the following congeners:

6-propionamido-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-octanamido-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-acrylamido-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(3-methylacrylamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(3,3-dimethylacrylamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-cyclopentylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-cyclohexylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-cycloheptylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[cyclohex-3-enyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[cyclohex-1-enyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(o-methoxybenzamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,6-dimethoxybenzamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,6-diethoxybenzamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,6-dipropoxybenzamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,6-dibutoxybenzamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-methoxy-1-naphthamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-ethoxy-1-naphthamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-n-butoxy-1-naphthamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(4-isothiazolecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-imidazolecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-azido-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(3-phenylpropionamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[phenylthio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[3-sydnonyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[3-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[2-furyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[3-methyl-2-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[1-pyrazolyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[1,2,4-triazol-1-yl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[2,4-dimethylthiazol-5-yl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[N-methylpyrrol-2-yl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[1-pyrrolyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[p-chlorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[m-methoxyphenyl)acetamido]-2,2-dimethyl-3-(5-tetrazolyl)penam, and

6-(2-[p-tolyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

respectively.

The acid chlorides used in this Example are prepared from thecorresponding acids, using methods well known in the art (Buehler andPearson, "Survey of Organic Syntheses," Wiley-Interscience, 1970, pp.859-867). 2-(Cycloheptyl)acetic acid and 2-cyclohex-1-enyl)acetic acidare prepared from their corresponding nitriles (which are items ofcommerce) by hydrolysis, using methods discussed by Buehler and Pearson(loc. cit., pp. 752-753). 2-(Cyclohex-b 3-enyl)acetic acid is preparedby the method of Boehme, Journal of Organic Chemistry, 26, 2107 (1961).The 2,6-dialkoxybenzoic acids are prepared according to Doyle, et al.,Journal of the Chemical Society (London), 1453 (1962), and the2-alkoxy-1-naphthoic acids according to British Pat. No. 880,400.2-(3-Sydnonyl)acetic acid is prepared by the method of Stewart,Chemistry and Industry (London), 1411 (1961). The 2-(3-thienyl)aceticacid, 2-(2-furyl)acetic acid, 2-(3-methyl-2-thienyl)acetic acid,2-(1-pyrazolyl)acetic acid, 2-(1,2,4-triazol- 1-yl)acetic acid,2-(2,4-dimethylthiazol-5-yl)acetic acid, 2-(N-methylpyrrolyl)acetic acidand 2-(1-pyrrolyl)acetic acid are prepared by methods disclosed inBelgian Pat. No. 618,663. All the other acids are items of commerce.

EXAMPLE LV6-(3-[Carbamoyl]acrylamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred mixture of 1.15 g. (10 m mole) of maleamic acid and 1.40ml. of triethylamine in 40 ml. of dry tetrahydrofuran, at 0° C., isadded 1.57 ml (12 m mole) of isobutyl chloroformate followed by threedrops of N-methylmorpholine. Stirring is continued for a further 30minutes at 0° C. To this mixed anhydride is then added a solutionprepared by adding 2.40 g. (10 m mole) of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam to a mixture of 15 ml. ofwater and 15 ml. of tetrahydrofuran and adjusting the pH to 7.5. Theresulting mixture is then stirred for a further 1 hour at 0° C. At thispoint, the tetrahydrofuran is removed by evaporation in vacuo, and theresidue is diluted with more water. The pH is adjusted to 8.0 with 6 Nsodium hydroxide, and then the mixture is extracted with ethyl acetate.The extracts are discarded. The pH of the residual aqueous phase isadjusted to 2.0 with 4 N hydrochloric acid and then the product isextracted into ethyl acetate. The organic layer is dried andconcentrated in vacuo to give6-(3-[carbamoyl]acrylamido)-2,2-dimethyl-3-(5-tetrazolyl)penam (1.03 g.,33% yield). The infrared spectrum (KBr disc) of the product showsabsorption band at 1818 cm⁻¹ (β-lactam) and 1692 cm⁻¹. The NMR spectrum(DMSO-d₆) shows bands at 7.00 and 6.25 (quartet, 2H, J=12 Hz, olefinichydrogens), 5.80-5.48 ppm (multiplet, 2H, C-5 and C-6 hydrogens), 5.26ppm (singlet, 1H, C-3 hydrogen), 1.65 ppm (singlet, 3H, C-2 methylhydrogens) and 1.06 ppm (singlet, 3H, C-2 methyl hydrogens).

EXAMPLE LVI 6-Formamido-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 480 mg. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam and 0.56 ml. of triethylaminein 5 ml. of methylene chloride, at 0° C., is added 0.3 ml. of formicacetic anhydride. Stirring is continued for a further 45 minutes, at 0°C., and then the solvent is removed by evaporation in vacuo. The residueis partitioned between water and ethyl acetate, and then the ethylacetate is separated off and dried. Evaporation of the ethyl acetate invacuo affords 0.216 g. of 6-formamido-2,2-dimethyl-3-(5-tetrazolyl)penamas a foam. The NMR spectrum (CDCl₃) shows absorptions at 8.20 ppm(singlet, 1H, formamido hydrogen), 5.80 ppm (multiplet, 2H C-5 and C-6hydrogen), 5.30 ppm (singlet, 1H, C-3 hydrogen), 1.70 ppm (singlet, 3H,C-2 methyl hydrogens) and 1.10 ppm (singlet, 3H, C-2 methyl hydrogens).The infrared spectrum of the sodium salt (KBr disc) shows absorptions at1760 cm⁻¹ and 1660 cm⁻¹.

EXAMPLE LVII 6-(2-Bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred suspension of 3.0 g (0.0125 mole) of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 15 ml of water is added1.74 g (0.0125 mole) of bromoacetic acid dissolved in 5 ml of water. ThepH of the mixture is adjusted to 6.0 using 20% sodium hydroxidesolution. The resulting clear solution is cooled to 0° C., and then 2.4g (0.0125 mole) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride is added. The solution is stirred at 0° C. for a further2.5 hr, during which time the pH is maintained between 6 and 7 by theaddition of 6 N hydrochloric acid. At this point, the pH is adjusted to7.0 and the reaction mixture is extraced with ethyl acetate. The extractis discarded. The pH of the reaction mixture is then lowered to 2.0 (6 Nhydrochloric acid), and the product is extracted into ethyl acetate. Theethyl acetate is washed with water, dried, and evaporated to give 3.2 g(72% yield) of 6-(2-bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamas a white foam. The infrared spectrum (KBr disc) of the product showsabsorption bands at 1795 cm⁻¹ (β-lactam), 1670 cm⁻¹ (amide I) and 1530cm⁻¹ (amide II). The NMR spectrum (CDCl₃) shows absorption bands at10.6-9.6 ppm (broad singlet, tetrazole hydrogen), 8.8 ppm (doublet,amide hydrogen), 5.8-5.4 ppm (multiplet, C-5 and C-6 hydrogens), 5.35ppm (singlet, C-3 hydrogen), 4.0 ppm (singlet, methylene hydrogen), 1.90ppm (singlet, C-2 methyl hydrogens) and 1.15 ppm (singlet, C-2 methylhydrogens).

The above product is dissolved in 15 ml of water containing 1 equivalentof sodium bicarbonate. The resulting solution is then lyophilizedleaving the sodium salt of the title compound (3.4 g, 72% yield).

EXAMPLE LVIII6-(2-[4-Pyridylthio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred suspension of 1.0 g (0.0028 mole) of6-(2-bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml ofmethylene chloride is added 0.28 g (0.0028 mole) of triethylamine. Themixture is stirred at ambient temperature until a clear solution isobtained, and then 0.39 g of 4-mercaptopyridine is added. Stirring iscontinued for a further 4 hours at ambient temperature, and then thesolid which has precipitated is filtered off. It is washed withmethylene chloride, followed by ether, to give 0.68 g (78% yield) of6(2-[4-pyridylthio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, m.p.120° C. (dec.). The infrared spectrum of the product (KBr disc) showsabsorption bands at 1790 cm⁻¹ (β-lactam), 1670 cm⁻¹ (amide II). The NMRspectrum (DMSO-d₆) show absorption bands at 9.0-7.0 ppm (multiplet,pyridine hydrogens), 5.9-5.5 ppm (multiplet, C-5 and C-6 hydrogen), 4.0ppm (singlet, methylene hydrogens), 1.7 ppm (singlet, C-2 methylhydrogens) and 1.1 (singlet, C-2 methyl hydrogens).

EXAMPLE LIX6-(2-[N,N-Diethylamidinothio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 1.40 g (0.039 mole) of6-(2-bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml ofmethylene chloride is added 0.54 ml (0.039 mole) of triethylamine,followed by 0.52 g (0.039 mole) of N,N-diethylthiourea. Stirring iscontinued for a further 45 minutes, and then the solvent is decantedfrom the oil which has separated. The oil is triturated with ether,giving a white solid, which is filtered off. The yield is 1.28 g (76% oftheory) of6-(2-[N,N-diethylamidinothio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam.The infrared spectrum (KBr disc) of the product shows absorption bandsat 1780 cm⁻¹ (β-lactam) and 1670 cm⁻¹ (amide I). The NMR spectrum(DMSO-d₆) shows absorption bands at 5.65 ppm (multiplet, C-5 and C-6hydrogens), 5.15 ppm (singlet, C-3 hydrogen), 4.10 ppm (singlet,methylene hydrogens), 3.45 ppm (quartet, ethyl hydrogens), 1.60 ppm(singlet, C-2 methyl hydrogens), 1.10 ppm (triplet, ethyl hydrogens) and1.00 ppm (singlet, C-2 methyl hydrogens).

EXAMPLE LX 5-(2,6-Dimethoxybenzamido)-2,2-dimethyl-3-(5-tetrasolyl)penam

To a stirred solution of 1.2 g. (5 mmole) of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 1.01 g. (10 mmole) oftriethylamine and 50 ml. of methylene chloride, is added 1.0 g. (5mmole) of 2,6-dimethoxybenzoyl chloride (Norris and Ware, J. Amer. Chem.Soc., 61, 1418 [1936], at ca. 0° C. Stirring is then continued for threehours at ambient temperature. To the reaction mixture is added 50 ml. ofwater, and the pH of the aqueous phase is adjusted to 8.0. The organicphase is separated off and discarded. The pH of the residual aqueousphase is lowered to 2.5, and the precipitate which forms is filteredoff. This affords 1.2 g. (59% yield) of the title compound, m.p. 215° C.(dec.). IR (KBr disc): 1808, 1643 and 1605 cm⁻¹. NMR (in D₂ O/Na HCO₃):7.50 ppm (t, 1H), 6.90 ppm (d, 2H), 5.90 and 6.0 ppm (q, 2H), 5.40 ppm(s, 1H), 4.00 ppm (s, 6H), 1.80 ppm (s, 3H) and 1.20 ppm (s, 3H).

EXAMPLE LXI6-(2-Ethoxy-1-naphthamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

Following the procedure of Example LX, the title compound is preparedfrom 2.84 g. (0.012 mol) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl) penamand 1.39 (0.006 mol) of 2-ethoxy-1-naphthoyl chloride and is isolated asthe sodium salt by standard procedures: yield 1.5 (54%); IR (KBr); 1780,1715, 1667 cm⁻¹ ; NMR (D₂ O) 8.0-6.8 ppm (m, 6H), 5.85 (s, 1H), 5.40 (s,1H), 5.25 (s, 1H), 3.90 (q, 2H), 1.45 (s, 3H), 1.25 (t, 3H) 1.00 (s,3H).

EXAMPLE LXII 6-Phenylpyruvamido-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 960 mg. (4 mmole) of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam and 1.2 g. (12 mmole) oftriethylamine in 20 ml. of methylene chloride, is added a solution of728 mg. (4 mmole) of phenylpyruvoyl chloride in 5 ml. of methylenechloride, at 0° C. The cooling bath is removed, and when the reactionmixture has attained room temperature, the solvent is removed byevaporation in vacuo. The residue is partitioned between ethyl acetateand water, the pH is adjusted to 7.8, and then the ethyl acetate layeris separated and discarded. The pH of the residual aqueous phase isadjusted to 2.5, and the product is extracted into ethyl acetate. Theethyl acetate is washed with water, followed by brine, and then driedusing sodium sulfate. To the ethyl acetate is added 404 mg. oftriethylamine, and then the solvent is evaporated to dryness in vacuo.This affords 1.26 g. (65% yield) of the title compound as itstriethylamine salt. IR (KBr disc); 1760 and 1670 cm⁻¹ . NMR (in CDCl₃):7.4-7.0 ppm (m, 5H); 6.0-5.2 ppm (m, 3H), 3.6 ppm (s, 2H), 1.6 ppm (s,3H), 1.1 ppm (s, 3H).

EXAMPLE LXIII

Following the procedure of Example LXII, and reacting either6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam or6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam withthe appropriate acid chloride, the following compounds are prepared:

    __________________________________________________________________________     ##STR36##                                                                                     Infrared                                                                  Yield                                                                             Spectrum                                                     R.sup.1      (%) (cm.sup.-1)                                                                         NMR Spectrum* (CDCl.sub.3 ; ppm)                       __________________________________________________________________________    ethoxycarbonyl                                                                             60  1780, 1710,                                                                         5.9-5.4(m), 5.38(s), 1.7(s), 1.1(s).                                    1515, 1270                                                   benzoyl      85  1785, 1670                                                                          8.4-7.5(m), 5.9-5.4(m), 5.38(s), 1.8(s), 1.2(s).       acetyl       58  1785, 1700,                                                                         6.0-5.4(m), 3,2(s), 3.1(s).                                             1640                                                         2-benzoylformamido)-                                                                       66  1785, 1670,                                                                         8.2-7.2(m,10H), 5.8(m,3H), 5.4(s,1H), 1.4(s,3H),                              0.9(s,3H).                                             2-phenylacetyl   1600                                                         2-(acetylformamido)-                                                                       37  1785, 1680                                                                          7.4(s,5H), 5.8-5.2(m,4H), 2.4(s,3H), 1.4(s,3H),                               1.0(s,3H).                                             2-phenylacetyl                                                                2-(ethoxycarbonylform-                                                                     78  1785, 1680                                                                          9.8-9.2(s), 8.8-8.1(s), 7.7-7.1(m), 5.9-5.2(m),                               4.6-4.0(q),                                            amido)-2-phenylacetyl                                                                          1.5(s), 1.0(s).                                              2-(phenoxycarbonyl-                                                                        60  1785, 1725,                                                                         5.8-5.2(m,4H), 1.5(s,3H), 1.0(s,3H).                   amido)-2-phenylacetyl                                                                          1600                                                         2-(ethoxycarbonyl-                                                                         80  1785, 1680                                                                          7.5-7.2(s,1H), 6.9-6.4(m,5H), 5.7-5.4(m,4H),                                  4.3-3.9(q,2H),                                         amino)-2-phenylacetyl                                                                          1.9(s,3H), 1.1(s,3H).                                        2-(benzyloxycarbonyl-                                                                      35  1785, 1680                                                                          7.4(s,5H), 7.3(s,5H), 5.8-5.1(m,4H),                                          3.2-2.8(q,2H), 1.9(s,3H),                              amino)-2-phenylacetyl  1.0(s,3H).                                             __________________________________________________________________________     *the absorption bands due to the triethylamine have been omitted from thi     tabulation.                                                              

EXAMPLE LXIV

Reaction of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam withthe appropriate acid chloride, according to the procedure of ExampleLXII, provides the following compounds, which are isolated as the freeacids by elimination of the final triethylamine treatment.

    __________________________________________________________________________     ##STR37##                                                                                         Melting                                                                            Infrared                                                             Yield                                                                             Point                                                                              Spectrum                                            R.sup.1          (%) (° C.)                                                                      (cm.sup.-1)                                                                         NMR Spectrum (DMSO-d.sub.6 /CDCl.sub.3 ;                                      pm)                                           __________________________________________________________________________    2-(2-phenylacetamido)-2-phenyl-                                                                77  130-140                                                                            1800,1655,                                                                          10.42(m,1H), 8.07(d,1H), 7.33(m,10H),                                         5.73(d,1H), 5.63(m,2H),                       acetyl                    1515  5.10(s,1H), 3.67(s,2H), 1.67(s,3H),                                           1.08(s,3H),                                   2-benzamido-2-phenylacetyl                                                                     65  145-165                                                                            1785,1640,                                                                          8.20(d,1H), 7.90(m,3H), 7.50(m,8H),                                           6.00(d,1H), 5.60(m,2H),                                                 1515  5.23(s,1H), 1.53(s,3H), 1.03(s,3H),           2-acetamido-2-phenylacetyl                                                                     74  140-160                                                                            1790,1655,                                                                          8.10(d,1H), 7.40(m,5H), 5.8(d,1H),                                            5.60(m,2H), 5.20(s,1H),                                                 1525  1.67(s,3H), 1.08(s,3H),                       2-butyramido-2-phenylacetyl                                                                    74  146-160                                                                            1795,1695,                                                                          8.84(t,1H), 8.07(d,1H), 7.50(m,5H),                                           5.90)d,1H), 5.70(m,2H),                                                 1650  5.27(s,1H), 2.27(t,2H), 1.87(m,5H),                                           1.07(m,6H),                                   2-(2-furancarboxamido)-2-                                                                      73  143-165                                                                            1795,1665                                                                           8.60(m,1H), 7.90(d,1H), 7.6-7.0(m,7H),                                        7.5(q,1H), 6.00(d,1H),                        phenylacetyl              1600,1515                                                                           5.60(m,2H), 5.23(s,1H), 1.58(s,3H),                                           1.03(s,3H),                                   2-(2-thiophenecarboxamido)-                                                                    88  130-155                                                                            1800,1695,                                                                          8.50(m,1H), 8.10(d,1H), 7.80-7.00(m,8H),                                      5.95(d,1H), 5.60(m,                           2-phenylacetyl            1640,1540,                                                                          2H), 5.10(s,1H), 1.60(s,3H), 1.10(s,3H),                                1505                                                2-(2-[2-thienyl]acetamido)-                                                                    69  134-148                                                                            1795,1655,                                                                          8.91(m,1H), 8.33(d,1H), 7.50-7.10(m,5H),                                      6.90(m,2H), 5.75(d,                           2-phenylacetyl            1530  1H), 5.60(m,2H), 5.20(s,1H), 3.83(s,2H),                                      1.60(s,3H), 1.05(s,3H),                       2-(3-pyridinecarboxamido)-                                                                     62  164-185                                                                            1785,1660,                                                                          9.10(s,1H), 8.70(m,3H), 8.30(m,1H),                                           7.50(m,7H), 6.00(d,1H),                       2-phenylacetyl            1600,1530                                                                           5.67(q,2H), 5.20(s,1H), 1.60(s,3H),                                           1.05(s,3H),                                   2-(2-yrrolecarboxamido)-                                                                       58  170-195                                                                            1795,1695                                                                           10.80(s,1H), 8.60(d,1H), 7.90(d,1H),                                          7.30(m,5H), 6.90(t,2H),                       2-phenylacetyl            1640,1560                                                                           6.20(m,2H), 5.23(s,1H), 1.53(s,3H),                                           1.00(s,3H),                                                             1515                                                2-(2-[4-bromophenyl]acetamido)-                                                                75  140-162                                                                            1800,1647                                                                           8.83(m,1H), 8.35(d,1H), 7.35(m,9H),                                           5.6(m,3H), 5.2(s,1H),                         2-phenylacetyl                  3.6(s,2H), 1.6(s,3H), 1.05(s,3H),             2-(2-[4-methoxyphenyl]acet-                                                                    70  134-150                                                                            1798,1652                                                                           8.67(m,1H), 7.83(d,1H), 7.4(m,7H),                                            6.95(d,2H), 5.9                               amido)-2-phenylacetyl           (d,1H), 5.67(m,2H), 5.32(s,1H),                                               3.88(s,3H), 3.68                                                              (s,2H), 1.72(s,3H), 1.17(s,3H),               2-(4-pyridinecarboxamido)-                                                                     52  160-180                                                                            1795,1666                                                                           9.33(m,2H), 8.75(m,4H), 7.8(m,2H),                                            7.4(m,5H), 6.0(d,1H),                         2-phenylacetyl                  5.65(m,2H), 5.2(s,1H), 1.6(s,3H),                                             1.05(s,3H),                                   2-(2-[4-nitrophenyl]acet-                                                                      49  145-170                                                                            1795,1653                                                                           8.6(m,2H), 8.1(d,2H), 7.4(m,7H),                                              5.7(m,3H), 5.2(s,1H),                         amido)-2-phenylacetyl           3.7(s,2H), 1.6(s,3H), 1.05(s,3H),             2-(2-[2-furyl]acetamido)-                                                                      73  165-184                                                                            1795,1653                                                                           9.0(m,1H), 8.1(d,1H), 7.4(m,6H),                                              6.3(m,2H), 5.8(d,1H),                         2-phenylacetyl                  5.6(m,2H), 5.23(s,1H), 3.73(s,2H),                                            1.7(s,3H), 1.12(s,3H),                        2-(4-nitrobenzamido)-2-                                                                        81  160-178                                                                            1795,1653                                                                           8.83(m,3H), 8.2(q,4H), 7.4(m,5H),                                             6.0(d,2H), 5.6(m,2H),                         phenylacetyl                    5.2(s,1H), 1.6(s,3H), 1.05(s,3H),             2-(2-phenoxyacetamido)-                                                                        77  120-128                                                                            1795,1667                                                                           8.6(m,1H), 8.07(d,1H), 6.8-7.6(m,10H),                                        5.9(d,1H), 5.6                                2-phenylacetyl                  (m,2H), 5.2(s,1H), 4.6(m,2H), 1.6(s,3H),                                      1.07(s,3H),                                   2-(2-cyanoacetamido)-2-                                                                            135-145                                                                            2250,1790                                                                           9.1(d,1H), 7.45(m,5H), 5.75(d,1H),                                            5.63(m,2H), 5.15(s,1H),                       phenyacetyl               1667  3.80(s,2H), 1.6(s,3H), 1.03(s,3H),            2-(2-azidoacetamido)-2-                                                                        41  138-147                                                                            2100,1795                                                                           7.5(m,5H), 5.93(d,1H), 5.73(m,2H),                                            5.17(s,1H), 4.12(s,2H),                       phenylacetyl              1667  1.67(s,3H), 1.1(s,3H),                        __________________________________________________________________________

EXAMPLE LXV6-(D-2-Amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

A stirred suspension of 200 mg. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 5 ml. of water is cooledto 0°-5° C. in an ice-bath. The pH is then adjusted to 7.0 using dilutesodium hydroxide solution. At this point, 274 mg. ofD-2-amino-2-phenylacetyl chloride hydrochloride (Hardcastle et al.,Journal of Organic Chemistry, 31, 897 [1966]) is added portionwiseduring 15 minutes at 0°-5° C., and with the pH maintained between 6 and7 by the addition of dilute sodium hydroxide. At the end of theaddition, the reaction mixture is stirred for a further 15 minutes andthen filtered. The pH of the mother liquors is adjusted to 4.4 withdilute hydrochloric acid, and then the solution is stored overnight inthe refrigerator. The solution is then filtered, and the mother liquorsare placed on a column of 25 g. of Sephadex LH-20 (Pharmacia FineChemicals, Inc.) made up in water. The column is eluted with water,taking fractions, and the composition of the fractions is assayed bythin-layer chromatography. The fractions containing the pure product arecombined, and evaporated under high vacuum to a volume of approximately1 ml. After this solution has been set aside for a short period, theproduct crystallizes out. It is filtered off, washed briefly with waterand dried. The yield is 55 mg. of pure6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, m.p.192°-196° C. The infrared spectrum (KBr disc) shows absorptions at 1770cm⁻¹ (β-lactam carbonyl), 1680 cm⁻¹ (amide I band) and 1520 cm⁻¹ (amideII band).

EXAMPLE LXVI

When the procedure of Example LXV is repeated, and theD-2-amino-2-phenylacetyl chloride hydrochloride used there is replacedby an equivalent amount of the appropriate acid chloride hydrochloride,the following compounds are produced.

(6-(DL-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-3-amino-2-phenylpropionamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[2-pyridyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[3-pyridyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[4-pyridyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[4-pyridylthio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[p-aminophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(1-aminocyclobutanecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(1-aminocyclopentanecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(1-aminocyclohexanecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl) penam,

6-(1-aminocycloheptanecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[m-(N-methylamino)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamand

6-(2-[p-(N-n-butylamino)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

respectively.

DL-2-Amino-2-phenylacetic acid, 2-pyridylacetic acid, 4-pyridylaceticacid and p-aminophenylacetic acid are items of commerce.DL-3-amino-2-phenylpropionic acid is prepared by the method of Testa etal., Annalen der Chemie, 614, 167 (1958), and (4-pyridylthio)acetic acidis prepared by the method described in Netherlands Pat. No. 6,912,855.The 1-aminocycloalkanecarboxylic acids are prepared by the method ofAlburn et al., Antimicrobial Agents and Chemotherapy, 586 (1967). Theamino-acids are converted into their acid chloride hydrochlorides bysequential treatment with hydrogen chloride gas and phosphorouspentachloride (Hardcastle et al., Journal of Organic Chemistry, 31 897[1966].

EXAMPLE LXVII

Acylation of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam with the acidchloride hydrochloride of 2-(N-methylamino)-2-phenylacetic acid,2-(N-ethylamino)-2-phenylacetic acid, 2-(N-isobutylamino)-2-phenylaceticacid, 2-(N-n-hexylamino)-2-phenylacetic acid,2-(N-methylamino)-2-(2-thienyl)acetic acid and2-N-methylamino)-2-(p-chlorophenyl)acetic acid, respectively, accordingto the procedure of Example LXV produces the following congeners:

6-(2[N-methylamino]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[N-ethylamino]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[N-isobutylamino]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[N-n-hexylamino]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

6-(2-[N-methylamino]-2-[2-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamand

6-(2-[N-methylamino]-2-[p-chlorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

respectively.

2-(N-Methylamino-2-phenylacetic acid is prepared by the method of Aragaet al. (Nippon Kagaku Zasshi, 86, 111 [1965]; Chemical Abstracts, 6216365 [1965]). The other amino-acids are prepared in analogous fashion,using the appropriate aldehyde and amine. Acid chloride hydrochloridesare prepared by the method of Hardcastle et al. (Journal of OrganicChemistry, 31, 897 [1966]).

EXAMPLE LXVIII6-(D-2-Amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl) penam

To a stirred solution of 23.8 ml. of ethyl chloroformate in 600 ml. ofacetone, is added 25 ml. of a 3% solution of N-methylmorpholine inacetone. The resulting solution is cooled to -40° C., and then 75.2 g.of sodium N-(2-methoxycarbonyl-1-methylvinyl)-D-2-amino-2-phenylacetateis added. The temperature is adjusted to -20° C. and stirring iscontinued for 28 minutes. The solution is re-cooled to -40° C., and anice-cold solution, prepared by suspending 60.0 g. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 250 ml. of water and thenadjusting the pH to 7.0, is added. The resulting solution is stirred for30 minutes without further cooling, and then the acetone is removed byevaporation in vacuo. To the aqueous residue is added an equal volume oftetrahydrofuran, and then, at 5° C. the pH is adjusted to 1.5 withdilute hydrochloric acid. The mixture is held at this temperature and pHfor 30 minutes, and then the tetrahydrofuran is removed by evaporationin vacuo. The aqueous residue is extracted with ethyl acetate, followedby ether, and the extracts are discarded. The pH of the remainingaqueous phase is raised to 5.4, and the product begins to crystallizeout. After 1 hour it is filtered off and dried. The crude yield is 68.8g.

The product is suspended in water at 25° C., and the pH is lowered to1.5. After stirring for a short period, the insoluble materials arefiltered off, and the filtrate is extracted with ether. The aqueoussolution is then cooled to 5° C., and the pH is adjusted to 5.2. Thesolid which precipitates is filtered off, giving 62.7 g. (58.7% yield)of 6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamtrihydrate, m.p. 201°-202° C., [α]_(D) ²⁵ +228.2 (1% in CH₃ OH). IR (KBrdisc): 1780 cm⁻¹ (β-lactam). NMR (in DMSO-d₆ /D₂ O): 7.60 ppm (s, 5H),5.70 ppm (d, 1H), 5.55 ppm (d, 1H), 5.20 ppm (s, 1H), 5115 ppm (d, 1H),1.50 ppm (s, 3H), 0.90 ppm (s, 3H).

Analysis--Calcd. for C₁₆ H₁₉ O₂ N₇ S. 3H₂ O (percent): C, 44.95; H,5.89; N, 22.94; S, 7.50. Found (percent): C, 45.01; H, 5.84; N, 22.81;S, 7.34.

The sodium N-(2-methoxycarbonyl-1-methylvinyl)-D-2-amino-2-phenylacetateis prepared from methyl acetoacetate and D-2-amino-2-phenylacetic acidby the procedure used by Long et al. (J. Chem. Soc., London, Part C,1920 [1971]) for the corresponding p-hydroxy compound.

EXAMPLE LXIX

The procedure of Example LXVIII is repeated, except that the sodiumN-(2-methoxycarbonyl-1-methylvinyl)-2-amino-2-phenylacetate is replacedby the appropriate α-amino acid, protected as its acetoacetic esterenamine derivative. This affords the following compounds. In someinstances, the products are purified by Sephadex chromatography of theirsodium salts.

    __________________________________________________________________________     ##STR38##                                                                                          Infrared                                                           Side-chain                                                                           Yield                                                                             Spectrum                                                R.sup.7    Configuration                                                                        (%) (cm.sup.-1)                                                                         NMR Spectrum (ppm)                                __________________________________________________________________________    m-hydroxyphenyl.sup.1                                                                    D       5  1776, 1686                                                                          7.55-6.73(m,4H), 5.72(d,1H), 5.44(d,1H),                                      5.24(s,1H), 5.12(s,1H), 1.37(s,3H), 0.90                                      (s,3H), (D.sub.2 O),                              3,4-dihydroxyphenyl                                                                      DL      3  1770, 1684                                                                          6.97(s,1H), 6.80(s,2H), 5.75-5.34(m,2H),                                      5.03(s,1H), 4.93 and 4.86(2s,1H), 1.56 and                                    1.50(2s,3H), 0.96 and 0.92(2s,3H).                                            (DMSO-d.sub.6)                                    p-methoxyphenyl                                                                          D      30  1775  7.56-6.90(q,4H), 5.60(m,2H), 5.16(s,1H),                                      5.10(s,1H), 4.77(m,2H), 3.84(s,3H), 1.56                                      (s,3H), 1.00(s,3H). (DMSO-d.sub.6).               p-hydroxyphenyl                                                                          L       7        7.35(d,2H), 6.85(d,2H), 5.68(d,1H), 5.50                                      (d,1H), 5.08(s,1H), 4.98(s,1H), 1.58(s,3H),                                   1.00(s,3H). (DMSO-d.sub.6 ).                      2-thienyl  D      28  1770  7.74-7.10(m,3H), 5.75-5.54(m,2H),                                             5.44(s,1H),                                                                   5.12(s,1H), 1.52(s,3H), 0.96(s,3H).                                           (DMSO-d.sub.6).                                   p-(N,N-dimethyl-                                                                         DL     27  1775, 1690                                                                          7.44-6.79(q,4H), 5.84-5.46(m,2H), 5.23-4.99       amino)phenyl                (m,2H), 2.94(s,6H), 1.59 and 1.50(2s,3H),                                     1.00 and 0.93(2s,3H). (DMSO-d.sub.6).             3-chloro-4-hydroxy-                                                                      D      44  1783  7.63-6.88(m,3H), 5.60(d,1H), 5.43(d,1H),          phenyl.sup.1                5.06(s,1H), 5.03(s,1H), 1.42(s,3H), 0.90                                      (s,3H). (DMSO-d.sub.6).                           p-chlorophenyl.sup.1 3                                                                   DL      7  1785, 1695                                                                          7.53(s,4H), 5.63(d,1H), 5.53(d,1H), 5.30                                      (s,1H), 3.20(q,6H), 1.63(s,3H), 1.26(t,9H),                                   1.06(s,3H). (D.sub.2 O).                          m-chlorophenyl.sup.1 3                                                                   DL     14  1780, 1700                                                                          7.43(m,4H), 5.76(m,1H), 5.50(m,1H), 5.28                                      (d,1H), 5.16(s,1H), 3.16(q,6H), 1.36(s,3H),                                   1.26(t,9H), 0.96(d,3H). (D.sub.2 O).              m-nitrophenyl.sup.1 3                                                                    DL     22  1785, 1666                                                                          7.8-8.6(m,4H), 5.9(m,1H), 5.5(d,1H),                                          5.15(s,1H), 5.10                                                              (s,1H), 3.10(q,6H), 1.7(s,3H), 1.3(t,3H),                                     1.0(s,3H)                                                                     (DMSO-d.sub.6 /D.sub.2 O).                        p-sulfamoylphenyl                                                                        DL         1775, 1650                                                                          8.2-7.2(m,4H), 5.8-5.3(m,2H), 5.2(s,1H),                                      5.10(s,1H),                                                                   1.5 and 1.3(d,3H) 1.0 and 0.7(d,3H)                                           (DMSO-d.sub.6 /D.sub.2 O).                        p-fluorophenyl                                                                           D          1775, 1650                                                                          8.0-7.0(m,4H), 6.7(d,1H), 6.5(d,1H), 5.2                                      (s,1H), 5.1                                                                   (s,1H), 1.4(s,3H) 0.9(s,3H) (DMSO-d.sub.6                                     /D.sub.2 O).                                      2-furyl    D      18  1780, 1695                                                                          7.5(m,1H), 6.5(m,2H), 5.8(s,1H), 5.5(m,2H),                                   5.3(s,1H),                                                                    1.6(s,3H), 1.0(s,3H) (D.sub.2 O).                 2-tetrahydrofuryl                                                                        D      50  1780, 1690                                                                          5.6(m,2H), 5.2(s,1H), 4.1(m,1H), 3.7(m,3H),                                   1.8(m,4H),                                                                    1.6(s,3H), 1.0(s,3H) (DMSO-d.sub.6 /D.sub.2                                   O).                                               3-pyridyl  DL         1775  9.0-8.6(m,2H), 8.1-7.7(m,1H), 7.7-7.4(m,1H),                                  5.8-5.5                                                                       (m,2H), 5.2-5.0(m,2H), 1.5(d,3H), 0.9(d,2H)                                   (DMSO-d.sub.6).                                   2-bromo-5-hydroxy-                                                                       DL     28  1780, 1690                                                                          7.56(m,2H), 7.03(m,1H), 5.76(m,1H), 5.56(m,       phenyl.sup.2                1H), 5.30(s,1H), 5.15(s,1H), 1.46(s,3H),                                      0.96(s,3H). (DMSO-d.sub.6 /D.sub.2 O).            m-fluorophenyl.sup.1                                                                     D      17  1780, 1670                                                                          7.58-7.23(m,4H), 5.33(d,1H), 5.26(d,1H),                                      5.16(s,1H), 5.10(s,1H), 1.43(s,3H), 0.90                                      (s,3H). (DMSO-d.sub.6 /D.sub.2 O).                hydrogen   --         1785  6.35(m), 5.76-5.46(m,2H), 5.12(s,1H), 3.71                                    (s,2H), 1.62(s,3H), 1.00(s,3H).                                               (DMSO-d.sub.6).                                   isopropyl  D      30  1775, 1680                                                                          5.85(d,1H), 5.55(d,1H), 5.35(s,1H), 3.9(m,                                    1H), 2.08(m,1H), 1.67(s,3H), 1.07(s,3H),                                      1.00(d,6H). (D.sub.2 O).                          benzyl     D      41  1775, 1680                                                                          7.36(s,5H), 5.73(d,1H), 5.53(d,1H), 5.35(s,                                   1H), 3.10(m,3H), 1.53(s,3H), 1.00(s,3H).          3-indolylmethyl                                                                          D      58  1775, 1680                                                                          7.30(m,5H), 5.42(d,1H), 5.30(d,1H),                                           5.23(s,1H),                                                                   3.80(m,1H), 3.20(m,2H), 1.33(s,3H), 0.94(s,                                   3H). (D.sub.2 O).                                 __________________________________________________________________________

The starting enamines are obtained by condensation of the appropriateglycine with methyl acetoacetate, according to the procedure of Long, etal. (Journal of the Chemical Society [London], Part C, 1920 [1971]).Those α-amino acids which are described in the literature are preparedby the published procedures. The new α-amino acids are prepared from thecorresponding aldehydes via a Strecker synthesis, techniques for whichare discussed by Greenstein and Winitz in "Chemistry of the AminoAcids," John Wiley and Sons, Inc., New York/London, 1961, pp. 698-700,and references cited therein. the Strecker synthesis produces DL aminoacids, which are resolved into their optical isomers by conventionalmeans (consult Greenstein and Winitz, loc. cit., pp. 715-755; Nishimura,et al., Nippon Kagaku Zasshi, 82, 1688 [1961] [Chemical Abstracts, 58,11464 (1963)]); and Belgian patent No. 795,874). See also British patentNo. 1,221,227.

5-(3-Pyridyl)hydantoin is prepared by the method of Henze and Knowles,J. Org. Chem., 19, 1127 (1954), and it is hydrolysed to2-amino-2-(3-pyridyl)acetic acid by the method described by Davis et al.(Archives Biochem and Biophys. 87, 88 [1960]) for the corresponding4-isomer.

EXAMPLE LXX

Starting with the appropriate 2-substituted sodiumN-(2-methoxycarbonyl-1-methylvinyl)-2-aminoacetate, and following theprocedure of Example LXVIII, the following compounds are prepared:

6-(D-2-amino-2-[p-fluorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(L-2-amino-2-[p-fluorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[o-chlorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(L-2-amino-2-[o-chlorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[m-bromophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

6-(L-2-amino-2-[m-bromophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

6-(D-2-amino-2-[m-chlorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(L-2-amino-2-[m-chlorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[p-chlorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(L-2-amino-2-[p-chlorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-[2,4-dichlorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-[3,4-dichlorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[o-fluorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-[o-fluorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[m-fluorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(L-2-amino-2-[m-fluorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[p-bromophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

6-(L-2-amino-2-[m-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[m-tolyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(L-2-amino-2-[m-tolyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-[p-isopropylphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[p-amylphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-[o-methoxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-[p-isopropoxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[m-butoxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(L-2-amino-2-[m-butoxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-[p-amyloxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[p-amyloxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-[3,4-dimethoxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-[3,5-dimethoxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-[p-methylthiophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-[p-isopropylthiophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[1,4-cyclohexadienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(L-2-amino-2-[1,4-cyclohexadienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-cyclopropylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-cyclopentylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-cyclohexylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-cycloheptylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-aminopropionamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-aminobutyramido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-aminovaleramido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-allylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-(2-butenyl)acetamido)-2,2-dimethyl(5-tetrazolyl)penam,

6-(L-2-amino-2-[3-thienyl]acetamido-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(L-2-amino-2-[2-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[3-furyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-3-[5-ethyl-2-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[3-hydroxymethyl)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(D-2-amino-2-[4-(hydroxymethyl)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(DL-2-amino-2-[4-isothiazolyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

respectively.

The starting 2-substituted sodiumN-(2-methoxycarbonyl-1-methylvinyl)-2-amino-acetates are obtained bycondensation of the appropriate 2-substituted glycines with methylacetoacetate, according to the procedure of Long, et al. (Journal of theChemical Society [London], Part C, 1920 [1971]). Those 2-substitutedglycines which are described in the literature are prepared by thepublished procedures. The new 2-substituted glycines are prepared fromthe corresponding aldehydes via a Strecker synthesis, techniques forwhich are discussed by Greenstein and Winitz in "Chemistry of the AminoAcids," John Wiley and Sons, Inc., New York/London, 1961, pp. 698-700,and references cited therein. The Strecker synthesis produces DL aminoacids, which are resolved into their optical isomers by conventionalmeans (consult Greenstein and Winitz, loc. cit., pp. 715-755; Nishimura,et al., Nippon Kagaku Zasshi, 82, 1688 [1961] [Chemical Abstracts, 58,11464 (1963)]).

EXAMPLE LXXI6-(D-2-Amino-2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 0.19 ml. of ethyl chloroformate in 15 ml. ofdry acetone, cooled to 0° C., is added 1 drop of N-methylmorpholine,followed by 576 mg. of sodiumN-(2-methoxycarbonyl-1-methylvinyl)-D-2-amino-2-(4-hydroxyphenyl)acetate(Long et al., Journal of the Chemical Society [London], Part C, 1920[1971]). The mixture is stirred for a further 30 minutes, and then it iscooled to about -35° C. To it is then added an ice-cold solution of thesodium salt of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, prepared byadding 10% sodium hydroxide to a suspension of 436 mg. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 5 ml. of water (to give apH of 7.8), followed by dilution with 25 ml. of acetone. The coolingbath is removed, and the reaction mixture is stirred for a further 30minutes. At this point, the acetone is removed by evaporation underreduced pressure, and then 20 ml. of methyl isobutyl ketone is added tothe aqueous residue. The two-phase system is cooled to 10° C., acidifiedto pH=0.9 with dilute hydrochloric acid, and then it is stirred at 10°C. for 1 hour. The methyl isobutyl ketone is removed and discarded. ThepH of the aqueous phase is raised to 6.6, and then it is stored in therefrigerator for 3 hours. The precipitate which forms is filtered off,giving 320 mg. of6-(D-2-amino-2-[4-hydroxyphenyl]acetamido-2,2-dimethyl-3-(5-tetrazolyl)penam.The infrared spectrum (KBr disc) of the product shows absorptions at1775 cm⁻¹ (β-lactam carbonyl) and 1680 cm⁻¹ (amide I band). The NMRspectrum (in DMSO-d₆ /D₂ O) shows absorptions at 7.35 and 6.85 ppm (2doublets, aromatic hydrogens), 5.60 ppm (quartet, C-5 and C-6hydrogens), 5.10 ppm (multiplet, benzyl hydrogen and C-3 hydrogen), 1.45ppm (singlet, C-2 methyl hydrogens) and 0.95 ppm (singlet, C-2 methylhydrogens).

EXAMPLE LXXII6-(D-2-Amino-2-[3-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

The procedure of Example LXXI is repeated, except that the sodiumN-(2-methoxy-carbonyl-1-methylvinyl)-D-2-amino-2-(4-hydroxyphenyl)acetateused therein is replaced by an equimolar amount ofN-(2-methoxy-carbonyl-1-methyl-vinyl)-D-2-amino-2-(3-thienyl)acetate.There is obtained a 38% yield of6-(D-2-amino-2-[3-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum of the product (KBr disc) shows absorptionsat 1770 cm⁻¹ (β-lactam carbonyl), 1680 cm⁻¹ (amide I band) and 1505 cm⁻¹(amide II band). The NMR spectrum (in DMSO-D₆ /D₂ O) shows absorptionsat 7.60-7.05 ppm (multiplet, aromatic), 5.70-5.35 (multiplet, C-5 andC-6 hydrogens), 5.30 and 5.10 ppm (2 singlets, methine hydrogen and C-3hydrogen), 1.50 ppm (singlet C-2 methyl hydrogens) and 0.95 ppm(singlet, C-2 methyl hydrogens).

The sodiumN-(2-methoxycarbonyl-1-methylvinyl)-D-2-amino-2-(3-thienyl)acetate usedin this Example is prepared from D-2-(3-thienyl)glycine and methylacetoacetate using the method described by Long, et al. (Journal of theChemical Society [London], Part C, 1920 [1971]) for the condensation ofD-2-(4-hydroxyphenyl)glycine with methyl acetoacetate. TheD-2-(3-thienyl)glycine is prepared from thiophene-3-aldehyde by aStrecker reaction, followed by resolution of the DL-2-(3-thienyl)glycineso produced into its optical antipodes (Nishimura et al., Nippon KagakuZasshi, 82 1688 [1961])(Chemical Abstracts, 58, 11464 [1963]).

EXAMPLE LXXIII6-(D-2-Amino-2-[4-aminophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

A mixture of 23.9 g. of D-2-amino-2-(4-aminophenyl)acetic aciddihydrochloride (United States patent No. 3,634,405), 45.4 ml. oftriethylamine and 90 ml. of methanol is stirred at 25° C. for 10minutes, and then it is heated under reflux for 30 minutes. It is cooledto 25° C. again, and 31.5 ml. of methyl acetoacetate is added. This newreaction mixture is stirred at ambient temperature for 20 minutes, andthen it is heated under reflux for 40 minutes. The cooled reactionmixture is then poured, with stirring into 3,000 ml. of ether. The solidwhich precipitates is filtered off and discarded. Removal of the solventby evaporation in vacuo leaves 42.3 g. (93% yield) of the requiredtriethylammoniumN,N'-bis(2-methoxycarbonyl-1-methylvinyl)-D-2-amino-2-(4-aminophenyl)acetate.

To 19.0 g. of the above bis-enamine in 200 ml. of tetrahydrofuran isadded with vigorous stirring 8 drops of N-methylmorpholine, followed by5.38 ml. of isobutyl chloroformate, at 0°-5° C. Stirring is continuedfor 1 hour at 0°-5° C. at the end of the addition. A solution is thenprepared by suspending 9.85 g. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 80 ml, if water, coolingto 0°-5° C., adding 6 N sodium hydroxide to give a pH of 7.5, andfinally diluting with 200 ml. of tetrahydrofuran. This latter solutionis then added to the above mixed anhydride solution at ca. -40° C. Theresulting mixture is stirred at 0°-5° C. for 1 hour. The pH is thenlowered to 2.0, and the stirring is continued for a further 30 minutesat 0°-5° C. At this point, the bulk of the tetrahydrofuran is removed byevaporation in vacuo, and then the residual aqueous phase is washedtwice with ethyl acetate. The aqueous phase is then cooled to 5° C.,adjusted to pH 6.0, filtered, and lyophilized. This affords the titlecompound in a crude state. It is purified by chromatography on SephadexLH-20. The final yield is 591 mg. (3.7%). IR (KBr disc): 1770 cm⁻¹. NMR(DMSO-d₆): 7.18 and 6.60 ppm (q, J=8 Hz, 4H), 5.61 and 5.50 ppm (q, J=4Hz, 2H), 5.03 ppm (s, 1H), 4.91 ppm (s, 1H), 1.51 ppm (s, 3H) and 0.95ppm (s, 3H).

EXAMPLE LXXIV6-(D-2-Amino-2-[3-aminophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 5.0 g. of D-2-amino-2-(3-nitrophenyl)aceticacid in 26 ml. of 1.0 N sodium hydroxide, at 5° C., is added 4.4 g. ofbenzyl chloroformate. Stirring is continued for 1 hour with the pH beingmaintained between 9 and 11. The reaction mixture is washed with ethylacetate, and then the pH is lowered to 2.0. The aqueous residue is thenextracted with ethyl acetate. The extract is dried using anhydroussodium sulfate, and then it is evaporated in vacuo to give 5.3 g. ofN-(benzyloxycarbonyl)-D-2-amino-2-(3-nitrophenyl)acetic acid, [α]_(D) ²⁴=-108° (C=1, CH₃ OH).

To a stirred suspension of 5.0 g. (15 mmole) of the abovebenzyloxycarbonyl derivative, and 3.6 g. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 70 ml. of water is addedsufficient 20% sodium hydroxide to adjust to pH to 6.0. The resultingsolution is cooled to 5° C., and to this is added a solution of 2.8 g.(15 mmole) of 1-ethyl-3,3'dimethylaminopropylcarbodiimide hydrochloridein 10 ml of water. The pH of the solution is maintained between 6.0-6.2for 2 hours. The reaction is then warmed to room temperature and the pHadjusted to 7.0. The solution is washed with 50 ml. of ethyl acetate andthe pH is then readjusted to 2.0 (6 N hydrochloric acid). The solutionis extracted with 300 ml. ethyl acetate, and the ethyl acetate layerdried and evaporated, to yield 3.5 grams of6-(2-[N-benzyloxycarbonylamino]-2-phenylacetamido-2,2-dimethyl-3-(5-tetrazolyl)penam.

A suspension of 3.4 g. of the above penam compound in 60 ml. of water isadjusted to pH 7.0 using 1.0 N sodium hydroxide. To the resultantsolution is added 3.4 g. of 10% palladium-on-carbon, and the mixture isshaken for 2 hours under an atmosphere of hydrogen at 50 psi. Thereaction mixture is then filtered, acidified to pH 2.0, and extractedwith ethyl acetate. The extracts are discarded, and the pH of theaqueous phase is adjusted to 5.5. The solution is then lyophilized. Theresidue is stirred with 30 ml. of N,N-dimethylformamide for 20 minutes,and then the insoluble material is removed by filtration and discarded.The filtrate is added dropwise to 800 ml. of hexane. The resultingprecipitate is collected by filtration to give 0.78 g. of6-(D-2-amino-2-[3-aminophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)-penam.IR (KBr disc): 1775 and 1650 cm⁻¹. NMR (DMSO-d₆ /D₂ O): 6.7-7.4 ppm (m,4H), 6.4-6.8 ppm (m, 2H), 5.10 ppm (s, 1H), 5.00 ppm (s, 1H) 1.50 ppm(s, 3H) 0.90 ppm (s, 3H). [α]_(D) ²⁴ =196 (C=0.1 1 N HCl).

EXAMPLE LXXV6-(2-[4-Aminomethylphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

Sodium 4-[(1-methoxycarbonyl-2-propenyl)aminomethyl]phenylacetate isprepared from 4-aminomethylphenylacetic acid [Zaugg and Horrom, J. Am.Chem. Soc. 80, 4317 (1958)] and methyl acetoacetate by the methoddescribed by Dane and Dockner [Chem. Ber., 98, 789 (1965)]. A suspensionof this salt (2.15 g, 7.5 mmole), 7 drops of N-methylmorpholine and 100ml. of tetrahydrofuran is stirred at -20° C.; ethyl chloroformate (0.81g. 7.5 mmole) is added and the mixture is stirred for 60 minutes.6-Amino-2,2-dimethyl-3-(5-tetrazolyl)penam (1.80 g., 7.5 mmoles) issuspended in a 50:50 mixture of tetrahydrofuran and water (40 ml), andthe pH is adjusted to 7.5 with 1 N sodium hydroxide solution whereby ahomogeneous solution is obtained. This is added to the above suspension,in one portion, the new mixture is stirred at -20° C. for 1 hour andthen it is allowed to warm to room temperature over 1 hour. Most of thetetrahydrofuran is removed in vacuo, the resultant aqueous solution iscooled in an ice bath, and the pH is adjusted to 1.5 with 3 Nhydrochloric acid. After 30 minutes the pH is adjusted to 2.5, and thesolution is extracted with ethyl acetate. The aqueous phase is adjustedto pH 6.0 and freeze-dried. The resultant lyophylate is combined withthat from another preparation (5 mmoles) and chromatographed on SephadexLH-20 (150 g) eluting with water. Like fractions (tlc analysis) arecombined and freeze-dried, yielding the title compound as a colorlessamorphous solid (570 mg., 11% yield), m.p. 190°-200° C. IR(KBr): 1770,1650 and 1515 cm⁻¹. NMR (DMSO-d₆ -D₂ O): 7.4 ppm (s, 4H), 5.65 ppm (d,J=4 Hz, 1H), 5.45 ppm (d, J=4 Hz, 1H), 5.2 ppm (s, 1H), 4.1 ppm (s, 2H),3.6 ppm (s, 2H), 1.6 ppm (s, 3H) and 1.0 ppm (s, 3H).

When the above procedure is repeated and the 4-aminomethylphenylaceticacid is replaced by an equimolar amount of 3-(2-aminoethyl)phenylaceticacid, 4-(2-aminoethyl)-phenylacetic acid,5-(2-aminoethyl)-1-tetrazolylacetic acid and5-(2-aminoethyl)-2-tetrazolylacetic acid, respectively, there isobtained:

6-(2-[3-(2-aminoethyl)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[4-(2-aminoethyl)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[5-(2-aminoethyl)-1-tetrazolyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamand

6-(2-[5-(2-aminoethyl)-2-tetrazolyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

respectively.

EXAMPLE LXXVI6-(2-[2-Azidomethylphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

A stirred suspension of 21.73 g. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 400 ml. of a 50:50 mixtureof tetrahydrofuran-water is cooled to ca. 0° C. and the pH is adjustedto 7.5 using 1.0 N sodium hydroxide. To the solution thus obtained, isadded 17.3 g. of 2-(2-azidomethylphenyl)acetic acid (U.S. Pat. No.3,766,175), followed by 17.4 g. of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The pHdrops to 5.5. The reaction mixture is then stirred at ambienttemperature, at pH 6, for 3 hours. At this point, the bulk of thetetrahydrofuran is removed by evaporation in vacuo, and the residualaqueous phase is extracted with ethyl acetate. The organic extract isdiscarded and the aqueous phase is cooled to ca. 0° C. The pH is thenadjusted to 2 and the product is extracted into ethyl acetate. The ethylacetate is dried and evaporated, leaving 34.8 g. of the title compoundas a tan solid. IR(CHCl₃) 2100, 1790, 1680 and 1515 cm.⁻¹ NMR (DMSO-d₆):7.37 (s, 4H), 5.60 (m, 2H, 5.23 (s, 1H), 4.55 (s, 2H), 3.70 (s, 2H),1.66 (s, 3H) and 1.06 ppm (s, 3H).

The above product is dissolved in 400 ml. of 50:50 tetrahydrofuran-waterat ca. 0° C. and the pH is adjusted to 7.0 with 1.0 N sodium hydroxide.The tetrahydrofuran is removed by evaporation under reduced pressure,and the residual aqueous phase is lyophilized to give 28.8 g. (73%yield) of the title compound as its sodium salt.

EXAMPLE LXXVII6-[2-[o-(aminomethyl)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred mixture of 2.25 g. of sodiumN-(1-methyl-2-methoxycarbonylvinyl)-2-(o-[aminomethyl]phenyl)acetate and2 drops of N-methylmorpholine in 20 ml. of tetrahydrofuran, at -10° C.,is added 0.856 g. of ethyl chloroformate. Stirring is continued for afurther 15 minutes at ca. -5° C., and then the mixture is cooled to -30°C. To this mixture is then added a solution prepared by adding 1.68 g.of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam to 20 ml. of 1:3water-tetrahydrofuran and adjusting the pH to 7.0. After the addition,the cooling bath is removed, and the reaction mixture is allowed to warmto ambient temperature. The tetrahydrofuran is removed by evaporation invacuo, and 15 ml. of tetrahydrofuran are added to the aqueous residue.The pH is adjusted to 1.5, and then the mixture is stirred at this pHfor 30 minutes. The pH is then raised to 3.0 and the tetrahydrofuran isremoved by evaporation in vacuo. The aqueous residue is washed withethyl acetate, and then the aqueous solution is concentrated to smallvolume. The solid which precipitates is filtered off giving 0.52 g. of6-(2-[o-(aminomethyl)phenyl]acetamido]-2,2-dimethyl-3-(5-tetrazolyl)penam.The infrared spectrum of the product (KBr disc) shows absorptions at1780 cm⁻¹ (β-lactam) and 1645 cm⁻¹. The NMR spectrum (DMSO-d₆ /D₂ O)shows absorptions at 7.45 ppm (singlet, 4H), 5.60 ppm (quartet, 2H),5.10 ppm (singlet, 1H), 4.10 ppm (singlet, 2H), 3.80 ppm (singlet, 2H),1.65 ppm (singlet, 3H), and 0.95 ppm (singlet, 3H).

The starting sodiumN-(1-methyl-2-methoxycarbonylvinyl)-2-(o-[aminomethyl]phenyl)acetate isprepared from 2-(o-[aminomethyl]phenyl)acetic acid (U.S. Pat. No.3,766,175) and methyl acetoacetate using the method to Long et al.(Journal of the Chemical Society [London], Part C, 1920 [1971]) for thecondensation of D-2-(p-hydroxyphenyl)glycine with methyl acetoacetate.cl EXAMPLE LXXVIII

6-(2-[3-Azidomethyl-2-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam(A) 3-Bromomethyl-2-thienyl Methyl Ketone.

A mixture of 14 g. (0.1 mole) of 3-methyl-2-thienyl methyl ketone(Hartough and Kosak; J. Amer. Chem. Soc., 69, 3093 [1947]), 18 g. (0.1mole) of N-bromosuccinimide, 0.3 g. of azoisobutyronitrile and 300 ml.of carbon tetrachloride is heated under reflux for 4 hours. The cooledreaction mixture is filtered, and the filtrate is washed with saturatedsodium bicarbonate solution and then dried. Evaporation of the solventin vacuo leaves a solid, which is recrystallized from hexane, giving 16g. (73% yield) of the bromomethyl compound, m.p. 62°-64° C.

(B) 3-Azidomethyl-2-thienyl Methyl Ketone.

To a solution of 5 g. (0.023 mole) of the above bromomethyl compound in42 ml. of acetone and 4 ml. of water is added 1.56 g. (0.026 mole) ofsolid sodium azide. After the exothermic reaction subsided, the mixtureis stirred for 2.5 hours at ambient temperature. The acetone is removedby evaporation, the residue is diluted with water, and the product isextracted into ether. The extract is washed with sodium bicarbonatesolution, dried, and evaporated to give 4 g. (97% yield) of theazidomethyl compound as a yellow oil.

(C) 2-(3-Azidomethyl-2-thienyl)acetic Acid.

To a solution of 20.5 g. (0.113 mole) of the above azidomethyl compoundin 230 ml. of methanol and 46 ml. of 70% aqueous perchloric acid, isadded 55.1 g. (0.124 mole) of thallium (III) nitrate. The mixture isstirred at ambient temperature for 24 hours, and then 0.18 mole ofsodium chloride is added. After 15 minutes, the reaction mixture isfiltered and the filtrate is concentrated to half volume. A 150-ml.quantity of water is added and the solution is again concentrated tohalf volume. A further 150-ml. quantity of water is added and themixture is extracted with ether. The extracts are washed with sodiumbicarbonate solution, dried, and evaporated giving crude methyl2-(3-azidomethyl-2-thienyl)acetate. This product is purified bychromatography on florisil. Yield 17.2 g. (72%).

A solution of 15.6 g. of the above ester in 200 ml. of tetrahydrofuranand 30 ml. of 3 N hydrochloric acid is heated under reflux for 5 hours.The cooled solution is then basified to pH 10 and the mixture isextracted with ether. The ether is discarded and the pH of the residualaqueous phase is lowered to 2. The product is then extracted into ether.The ether is dried and evaporated to give 10.5 g. (72% yield) of theacid as an oily solid.

(D)6-(2-[3-Azidomethyl-2-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam.

A solution of 5.48 g. (0.0228 mole) of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 200 m.l of 1:1tetrahydrofuran-water is adjusted to pH 7.5, and then 4.5 g. (0.0228mole) of 2-(3-azidomethyl-2-thienyl)acetic acid is added. The mixture iscooled to 0°-5° C., and 4.37 g. (0.0288 mole) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride is added.The reaction mixture is stirred at pH 6 and at 0°-5° C. for 2.5 hours.At this point, the tetrahydrofuran is removed by evaporation in vacuoand the pH is adjusted to 7.5. The aqueous residue is washed with ethylacetate and then the pH is lowered to 2.2. The product is extracted intoethyl acetate. The ethyl acetate is dried and evaporated in vacuo. Thisaffords 8.1 g. (88% yield) of the title compound as a foam. IR (KBrdisc): 2100, 1800, 1666, 1529 and 1250 cm⁻¹. NMR (CDCl₃): 7.3 (d, 1H),7.0 (d, 1H), 5.7 (m, 2H), 5.3 (s, 1H), 4.4 (s, 2H), 3.9 (s, 2H), 1.6 (s,3H) and 1.1 ppm (s, 3H).

EXAMPLE LXXIX6-(2-[3-Aminomethyl-2-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a solution of 1.68 g. (0.004 mole) of6-(2-[3-aminomethyl-2-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamin 100 ml. of water at pH 7.2 is added 3 ml. of dioxane and 600 mg. of10% palladium on carbon. The mixture is shaken under an atmosphere ofhydrogen at ca. 50 psi for 1.5 hours. The catalyst is then removed byfiltration, and the pH of the aqoueus phase is adjusted to 5.4. Theaqueous solution is then lyophilized to give the title compound in crudeform. It is purified by chromatography using Sephadex and eluting withwater. The purified products weighs 340 mg. 122% yield) and has m.p.187°-195° C. (dec.). IR(KBr disc) 330, 1770, 1650, 1530 and 1315 cm.⁻¹.NMR (D₂ O): 7.4 (d, 1H), 7.1 (d, 1H), 5.75 (d, 1H), 5.5 (d, 1H), 5.3 (s,1H), 4.2 (s, 2H), 4.0 (s, 2H), 1.55 (s, 3H) and 1.0 ppm (s, 3H).

EXAMPLE LXXX6-(2-[5-Azidomethyl-2-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

The title compound is prepared from 5-methyl-2-thienyl methyl ketone(Hartough and Kosak, J. Amer. Chem. Soc., 69, 3093 [1947]) using theprocedure of Example LXXVIII. IR (KBr disc): 3300, 2102, 1790, 1665 and1540 cm⁻¹. NMR (CDCl₃): 6.9 (m, 2H), 5.7 (m, 2H), 5.25 (s, 1H), 4.4 (s,2H), 3.8 (s, 2H), 1.6 (s, 3H) and 1.05 ppm (s, 3H).

EXAMPLE LXXXI6-(2-[5-Aminomethyl-2-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

Hydrogenation of6-(2-[5-azidomethyl-2-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,according to the procedure of Example LXXIX, gives a 23% yield of thetitle compound. IR(KBr disc): 3330, 1785, 1665 and 1530 cm⁻¹. NMR (D₂O): 7.0 (q, 2H), 5.8 (d, 1H), 5.5 (d, 1H), 5.4 (s, 1H), 4.35 (s, 2H),3.9 (s, 2H), 1.6 (s, 3H) and 1.0 ppm (s, 3H).

EXAMPLE LXXXII6-(2-[2-(aminomethyl)phenylthio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

The title compound is prepared in 14% yield, as a colorless amorphoussolid, by acylation of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam with2-(2-[aminomethyl]phenylthio)acetic acid (U.S. Pat. No. 3,766,176),using the method of Example LXXVII. IR(KBr disc): 1780 and 1665 cm⁻¹.NMR (DMSO-d₆ /D₂ O): 7.50 ppm (m, 4H), 5.70 ppm (d, 1H), 5.43 ppm (d,1H), 5.19 ppm (s, 1H), 4.35 ppm (s, 2H), 3.94 ppm (s, 2H), 1.60 ppm (s,3H), and 1.00 ppm (s, 3H).

EXAMPLE LXXXIII6-(1-Aminocyclohexanecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

The pH of a stirred suspension of 720 mg. (3.0 mmole) of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 50 ml. of water, at 0° C.,is adjusted to 7 using 1.0 N sodium hydroxide. When all the solid hasdissolved, the pH is lowered to 6.0 (1.0 N hydrochloric acid), and then750 mg. (3.4 mmole) of 2,4-oxazaspiro[4.5]decane-1,3-dione (Alburn, etal., Antimicrobial Agents and Chemotherapy, 586 [1967]) is added. Thereaction mixture is stirred at ca. 0° C., and at pH 6, for 1 hour. It isthen filtered. The pH is adjusted to 4.2, and the reaction islyophilized. The residue is dissolved in 5 ml. of methylene chloridecontaining 606 mg of triethylamine. This new solution is added dropwisewith stirring to 100 ml of ether, and the solid which precipitates isfiltered off. This affords 1.3 g (93% yield) of a 2:1 complex of thetitle compound and triethylamine. IR (KBr disc): 1786, 1680 and 1640cm⁻¹. NMR (in D₂ O): 5.90 ppm (d, 1H), 5.40 ppm (d, 1H), 5.30 ppm (s,1H), 3.10 ppm (q, 3H), 1.90-1.50 ppm (m, 10H), 1.60 ppm (s, 3H), 1.20ppm (t, 4.5H), 1.00 ppm (s, 3H).

EXAMPLE LXXXIV6-(D-2-Amino-2-[1,4-cyclohexadienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

Following the procedure use to prepare6-(1-aminocyclohexanecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl)penam(Example LXXXIII) the title compound is prepared from 0.5 g (2.8 mmole)of D-4-(1,4-cyclohexadienyl)-1,3-oxazolidin-2,5-dione and6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam; the product is isolated as a1:2 complex with triethylamine: yield 520 mg (36%); IR (KBr) 1779, 1678cm⁻¹. NMR (in D₂ O): 6.10 ppm (s, 1H), 5.80 (s, 2H), 5.90 ppm (d, 1H),5.60 ppm (d, 2H), 5.40 ppm (s, 1H), 4.50 ppm (s, 1H), 3.30 ppm (q, 12H),2.80 ppm (broad s, 4H), 1.70 ppm (s, 3H), 1.40 ppm (5, 18H), 1.20 ppm(s, 3H).

D-4-(1,4-cyclohexadienyl)-1,3-oxazolidin-2,5-dione is prepared from 2.0g (13.1 mmole) D-2-(1,4-cyclohexadienyl)glycine (Dolfini et al., J. Med.Chem. 14, 117 [1971]) and phosgene by the method described by Alburn, etal. [Antimicrobial Agents and Chemotherapy, 586 [1967]): yield 1.2 g(51%).

EXAMPLE LXXXV6-(D,L-3-Amino-2-phenylpropionamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

Sodium D,L-3-([1-methoxycarbonyl-2-propenyl]amino)-2-phenylpropionate isprepared from DL-3-amino-2-phenylpropionic acid [Testa, Fava andFontanella, Annalen, 614, 167 (1958)] and methyl acetoacetate by themethod described by Dane and Dockner [Chem. Ber., 98, 789 (1965)]. Asuspension of 1.43 grams (5 mmole) of this salt, one drop ofN-methylmorpholine, 5 ml. of tetrahydrofuran and 30 ml. ofdichloromethane is stirred at 0° C.; 0.6 grams (5 mmole) of2,2-dimethylpropionyl chloride is then added, and the mixture is stirredfor 30 minutes. A solution of 1.2 grams (5 mmole) of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 1.01 grams (10 mmole) oftriethylamine, and 30 ml. of dichloromethane is added to the suspension,and the new mixture is cooled and stirred for two hours. The volatilecomponents are evaporated under reduced pressure, and the residue isdissolved in 60 ml. of water. This mixture is stirred and cooled in anice bath while it is adjusted to pH 2.7 by the addition of 1 Nhydrochloric acid. After an hour some gummy material is filtered, andthe filtrate is cooled and is adjusted to pH 4.5 by the addition of 2 Nsodium hydroxide. After stirring the new mixture for 30 minutes anothersmall amount of solid matter is filtered, and the filtrate islyophilized. The lyophilate is slurried in 50 ml. of dichloromethane andthis mixture is filtered. The insoluble portion is dissolved in 100 ml.of dichloromethane and 4 ml. of triethylamine; a small amount ofinsoluble matter is filtered, and the filtrate is evaporated. Theresidue from the filtrate is triturated under ether to furnish the titlecompound as an amorphous 1:3 complex with triethylamine: yield 600 mg.(17%). IR (KBr disc): 1792, 1681 and 1618 cm⁻¹. NMR (in D₂ O): 7.50 ppm(s,5H), 5.80 ppm (d,1H), 5.60 ppm (d,1H), 5.30 ppm (s,1H), 4.20-3.50 ppm(m,3H), 3.30 ppm (q,18H), 1.50 ppm (s,3H), 1.30 ppm (t,27H), 1.00 ppm(s,3H).

Using the above procedure,6-(L-2-amino-3-[4-hydroxyphenyl]propionamido)-2,2-dimethyl-3-(5-tetrazolyl)penamis prepared as its sodium salt from 1.5 g. of sodiumN-(1-methoxycarbonyl-2propenyl)-L-2-(4-hydroxyphenyl)propionate and 1.2g. of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam. The crude product ispurified by chromatography using 25 g. of LH 20 grade dextran gel as thecolumn packing, and eluting with water. The final yield is 90 mg. IR(KBrdisc): 1780, 1688 and 1620 cm⁻¹. NMR (in D₂ O): 6.9 ppm (q,4H), 5.7 ppm(d,1H), 5.4 ppm (d,1H), 5.2 ppm (s,1H), 3.1-2.7 ppm (m,3H), 1.4 ppm(s,3H) and 1.0 ppm (s,3H).

EXAMPLE LXXXVI6-(2-[2-(2-Aminoethoxy)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

The title compound is prepared in 64% yield from2-(2-[2-aminoethoxy]phenyl)acetic acid (U.S. Pat. No. 3,759,905) and6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, by a procedure analogous tothat of Example LXXXV. IR (KBr disc): 1780 cm⁻¹ (β-lactam) and 1667 cm⁻¹(amide I). NMR (in D₂ O): 7.1 ppm (m,4H), 5.7 ppm (d,1H), 5.5 ppm(d,1H), 5.2 ppm (s,1H), 3.7-3.3 ppm (m,4H), 3.1 ppm (q,12H), 1.6 ppm(s,3H), 1.2 ppm (t,18H), 1.0 ppm (s,3H). The product is a 1:2 complex ofthe title compound and triethylamine.

EXAMPLE LXXXVII6-(2-[3-(2-Aminoethoxy)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

The title compound is prepared in a manner analogous to that used tomake its isomer6-(2-[2-(2-aminoethoxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam(Example LXXXVI, and consists of a 1:1 molar ratio of the tetrazoleproduct to triethylamine. The starting material,2-[3-(2-aminoethoxy)phenyl]acetic acid, is obtained by the proceduredescribed in U.S. Pat. No. 3,579,905. On a 3.5 mmol scale the yield is600 mg. (33%): IR (KBr) 1780 and 1660 cm⁻¹ ; NMR (D₂ O--NaHCO₃) 7.4-6.7ppm (m,3H), 5.70 (d,1H), 5.40 (d,1H), 5.25 (s,1H), 4.35-4.00 (m,2H),3.70-3.35 (m,4H), 3.15 (q,6H), 1.50 (s,3H), 1.25 (t,9H), 0.95 (s,3H).

EXAMPLE LXXXVIII6-(2-[4-(2-Aminoethoxy)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

The title compound is prepared in a manner analogous to that used tomake its isomer6-(2-[2-(2-aminoethoxy)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam(Example LXXXVI), and consists of a 3:1 molar ratio of the tetrazoleproduct to triethylamine. The starting material,2-[4-(2-aminoethoxy)phenyl]acetic acid is obtained by the proceduredescribed in U.S. Pat. No. 3,759,905. On a 5.0 mmol scale the yield is1.35 g. (60%): IR (KBr) 1785 and 1667 cm⁻¹ ; NMR (D₂ O) 7.10 ppm (q,4H),5.75 (d, 1H), 5.40 (d,H), 5.30 (s,1H), 4.40-4.05 (m,2H), 3.7-3.4(m,4H),3.20(q,2H), 1.60(s,3H), 1.35 (t,3H), 1.05 (s,3H).

EXAMPLE LXXXIX6-(2-[4-(2-Azidoethoxy)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

A stirred mixture of 1.2 g. (5 mmol) of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 1.1 (5 mmol) of4-(2-azidoethoxy)phenylacetic acid [U.S. Pat. No. 3,759,905], and 20 mlof water is adjusted to pH 7 by the careful addition of 6 N sodiumhydroxide. After a clear solution is obtained, the pH is adjusted to 6by the careful addition of 6 N hydrochloric acid. With ice-bath coolingand continuous stirring, the solution is treated with 0.96 g. (5 mmol)of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Thereaction solution is stirred, cooled and maintained at pH 6 for 90minutes. The solution is then adjusted to pH 6.9 and is washed twicewith 20-ml. portions of ethyl acetate. The aqueous solution is thenadjusted to pH 2.0, and the product is extracted into ethyl acetate. Theextract is then stirred with 20 ml. of water and the mixture is thenadjusted to pH 6.8. The aqueous phase is separated, and is thenlyophilized to furnish the title compound as its sodium salt: yield 1.31g(56%); IR (KBr) 2105, 1770 and 1660 cm⁻¹ ; NMR (D₂ O) 7.4-6.8 ppm (m,4H), 5.80 (d, 1H), 5.55 (d, 1H), 5.40 (s, 1H), 4.3-4.0 (m, 2H), 3.9-3.4(m, 4H), 1.55 (s, 3H), 1.00 (s, 3H).

EXAMPLE XC6-(D-2-[2-Aminoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To 0.418 g. of sodium N-(2-ethoxycarbonyl-1-methylvinyl)-2-aminoacetatein 10 ml. of tetrahydrofuran is added 2 drops of N-methylmorpholine and0.19 ml. of ethyl chloroformate with stirring. Stirring is continued fora further 30 minutes at -10° C. and then the solution is cooled to -30°C. To this solution is then added 0.708 g. of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamdissolved in 10 ml. of 1:1 tetrahydrofuran-water and adjusted to pH 8.7.Stirring is then continued for a further 30 minutes without cooling. Atthis point, the pH is adjusted to 1.5, and the reaction mixture isstirred at 0° C. for 30 minutes. The tetrahydrofuran is removed byevaporation in vacuo; and then the aqueous residue is washed with ether,washed with ethyl acetate, adjusted to pH 6.4 and lyophilized to give awhite solid. The solid is stirred for 20 minutes in 20 ml. ofN,N-dimethylformamide, and the solid which does not dissolve is filteredoff and discarded. The filtrate is added dropwise to 200 ml. ofchloroform, and the solid which precipitates is filtered off and driedgiving 0.3 g. (36.6% yield) of the title compound, m.p. 211°-230° C.(dec.). IR (KBr disc): 1770 cm⁻¹ (β-lactam). NMR (in DMSO-d₆): 9.50-9.15ppm (d, 2H), 7.40 ppm (s, 5H), 6.80-5.30 ppm (m, 9H), 5.00 ppm (s, 1H),3.65 ppm (s,2H), 1.50 ppm (s, 3H), 0.90 ppm (s, 3H).

EXAMPLE XCI6-(2-[2-Aminoacetamido]-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

The title compound is prepared in 45% yield from6-(2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamand sodium N-(2-ethoxycarbonyl-1-methylvinyl)-2aminoacetate, using theprocedure of Example XC. The product has m.p. 173°-188° C. (dec.). IR(KBr disc): 1785 cm⁻¹ (β-lactam). NMR (DMSO-d₆): 7.55-710 ppm (m, 2H),7.00-6.00 ppm (m, 2H), 5.75-5.40 ppm (m, 3H), 5.10 ppm (s, 1H), 3.65 ppm(m, 2H), 1.55 ppm (s, 3H), 0.95 ppm (s, 3H).

EXAMPLE XCII

Reaction of the appropriate6-(2-amino-2-substitutedacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam or6-(2-[2-aminoacetamido]-2-substitutedacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, with sodiumN-(2-ethoxycarbonyl-1-methylvinyl)-2-aminoacetate, according to theprocedure of Example XC, provides the following compounds:

    ______________________________________                                         ##STR39##                                                                      R.sup.7                 m                                                   ______________________________________                                        methyl                    0                                                   isopropyl                 0                                                   allyl                     0                                                   cyclohexyl                0                                                   3-cyclohexenyl            0                                                   1,4-cyclohexadienyl       0                                                   benzyl                    0                                                   p-chlorophenyl            0                                                   p-hydroxybenzyl           0                                                   m-bromophenyl             0                                                   p-fluorophenyl            0                                                   o-chlorophenyl            0                                                   3,4-dichlorophenyl        0                                                   3-chloro-4-hydroxyphenyl  0                                                   p-methoxyphenyl           0                                                   m-butoxyphenyl            0                                                   p-(hydroxymethyl)phenyl   0                                                   3,4-dimethoxyphenyl       0                                                   m-tolyl                   0                                                   2-thienyl                 0                                                   3-thienyl                 0                                                   2-furyl                   0                                                   3-furyl                   0                                                   3-pyridyl                 0                                                   5-ethyl-2-thienyl         0                                                   methyl                    1                                                   phenyl                    1                                                   p-hydroxyphenyl           1                                                   p-chlorophenyl            1                                                   ______________________________________                                    

EXAMPLE XCIII6-(D-2-[3-Aminopropionamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 0.95 ml. of ethyl chloroformate and 2 drops ofN-methylmorpholine, in 30 ml. of tetrahydrofuran, is added 2.39 g. ofN-(2-ethoxycarbonyl-1-methylvinyl)-3-aminopropionic acid, at -10° C.Stirring is continued for 30 minutes, and then the reaction mixture iscooled to 31 30° C. To it is then added a solution prepared bysuspending 3.8 g. of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamtrihydrate in 15 ml. of water and 15 ml. of tetrahydrofuran andadjusting the pH to 7.8. After the addition, the cooling bath is removedand stirring is continued for a further 30 minutes. The temperature ofthe reaction mixture is then adjusted to 0° C., the pH is adjusted 1.5,and stirring is continued for 30 minutes. At this point, thetetrahydrofuran is removed by evaporation in vacuo, the aqueous residueis extracted with ethyl acetate, and then the pH of the aqueous residueis adjusted to 6.0. Lyophilization of the aqueous residue then affordsthe crude product. It is purified by stirring with 400 ml. ofdimethylformamide, filtering, and added the filtrate slowly to 500 ml.of chloroform. The purified product is filtered off. The yield is 3.30g, mp 190° C. (dec.). IR (KBr disc): 1765 cm⁻¹. NMR (DMSO-d₆): 9.4-8.8ppm (m,2H), 8.0-7.1 ppm (m,10H), 5.9-5.3 ppm (m,3H), 5.0 ppm (s,1H),3.3-2.5 ppm (m,4H), 1.55 ppm (s,3H) and 0.9 ppm (s,3H).

EXAMPLE XCIV6-(2-[Benzamido]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 0.80 g. (2.7 mmole) of6-(2-aminoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and 0.453 g.(5.4 mmole) of sodium bicarbonate in 21 ml. of water and 15 ml. ofacetone at 0°-5° C. is added 0.32 ml. (2.8 mmole) of benzoyl chloride.Stirring is continued for a further 20 minutes at ca. 0° C., and thenthe acetone is removed in vacuo. The aqueous residue is extracted withethyl acetate and the extracts are discarded. The pH of the aqueousphase is adjusted to 2.0, and the product is extracted into ethylacetate. The solvent is dried (Na₂ SO₄), and then concentrated in vacuoto give 150 mg. (37% yield) of the title compound, m.p. 85°-93° C. IR(KBr disc): 1785 cm⁻¹ (β-lactam) and 1695 cm⁻¹ (amide I). NMR (in D₂ O):7.90 ppm (m,2 H), 7.50 ppm (m,3H), 5.82 ppm (s,1H), 5.58 ppm (s,1H),5.19 ppm (s,1H), 4.25 ppm (m,2H), 1.67 ppm (s,3H), 1.67 ppm (s,1H).

EXAMPLE XCV6-(2-[2-Bromoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred slurry of 4.27 g. (10 mmole) of6-(2-amino-2amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamin 25 ml. of water, at 0° C., is added 1.39 g. (10 mmole) of bromoaceticacid in 6 ml. of water. The pH is adjusted to 6.0, and then 1.9 g. (10mmole) of 1-ethyl-3-(dimethylaminopropyl)carbodimide hydrochloride in 9ml. of water is added. The mixture is stirred for 3 hours at pH 6. Atthis point, the pH is raised to 7.0, and the reaction mixture is washedwith ethyl acetate. The pH is then lowered to 2.0, and the product isextracted into ethyl acetate. The dried extracts are concentrated todryness in vacuo to give 2.0 g. (40% yield) of the title compound, m.p.128°-135° C. IR (KBr disc): 1800 cm⁻¹ (β-lactam) and 1653 cm⁻¹ (amideI). NMR (in DMSO-d₆ /D₂ O): 7.43 ppm (s,5H), 5.73 ppm (s,1H), 5.63 ppm(m,2H), 5.23 ppm (s,1H), 4.02 ppm (s,2H), 160 ppm (s,3H), 1.00 ppm(s,3H).

EXAMPLE XCVI6-(2-[2-(4-Pyridylthio)acetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 644 mg. of6-(2-[2-bromoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamin 15 ml. of N,N-dimethylformamide is added 45 mg. of 4-mercaptopyridinefollowed by 0.19 ml. of triethylamine. Stirring is continued for 3 hoursat 25° C., and then the reaction solution is added dropwise into 200 ml.of vigorously stirred chloroform. The precipitate is removed byfiltration, and the filtrate is added dropwise with stirring to 400 ml.of hexane. This causes the product to precipitate. After being slurriedwith methylene chloride, it weighs 228 mg. (33% yield), m.p. 182°-198°C. (dec.). IR (KBr disc): 1780 cm⁻¹ (β-lactam) and 1667 cm⁻¹ (amide I).NMR (DMSO-d₆ /D₂ O): 8.33 ppm (d,4H), 7.33 (s,5H), 5.60 ppm (m,3H), 5.15ppm (s,1H), 3.68 ppm (s,2H), 1.47 ppm (s,3H), 1.00 ppm (s,3H).

EXAMPLE XCVII 6-(2-[2-(Δ¹-Imidazolin-2-ylthio)acetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

The title compound is obtained in 73% yield by replacing the4-mercaptopyridine of Example XCVI with ethylene thiourea. The producthas m.p. 166°-175° C. (dec.). IR (KBr disc): 1785 cm⁻¹ (β-lactam), 1667cm⁻¹ (amide I). NMR (in D₂ O): 7.37 ppm (s,5H), 5.65 ppm (s,1H), 5.53ppm (m,2H), 5.23 ppm (s,1H), 3.62 ppm (s,2H), 3.50 ppm (m,4H), 1.42 ppm(s,3H), 0.87 ppm (s,3H).

EXAMPLE XCVIII6-(D-2-[2-Chloroacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 2.02 g. of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazol-5-yl)penamand 1.5 ml. of t riethylamine, in 25 ml. of dichloromethane, is added,dropwise, 0.48 ml. of chloroacetyl chloride, at 0° C. Stirring iscontinued for a further 2 hours at 0° C., and then the solvent isremoved by evaporation in vacuo. The residue is stirred with chloroformand recovered by filtration. This affords 1.16 g (48% yield) of thetitle compound, m.p. 142°-146° C. IR(KBr disc): 1780 and 1650 cm⁻¹. NMR(DMSO-d₆ /D₂ O): 7.47 ppm (m, 5H), 5.77 ppm (s, 1H), 5.67 ppm (m, 2H),5.25 ppm (s, 1H), 4.25 ppm (s, 2H), 1.63 ppm (s, 3H) and 1.02 ppm (s,3H).

EXAMPLE IC 6-(D-2-[2-Chloroacetamido]-2-[2-furyl]acetamido)-2,2-dimethyl3-(5-tetrazolyl)penam

To a solution of 10 drops of N-methylmorpholine in 40 ml. of acetone,cooled to -50° C., is added 0.30 ml. of ethyl chloroformate (3.2 mmole).After stirring 5 minutes at -50° C., a solution of 0.696 g. (3.2 mmole)of N-chloroacetyl-2-[2-furyl]glycine [αρ=-170° ethanol] and 0.44 ml. oftriethylamine (3.2 mmol), in 10 ml. of acetone, is added. The resultingsolution is stirred 10 minutes at -50° C. and then a solution preparedby suspending 0.72 g. (3 mmole) of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in a mixture of 12 ml. ofwater and 8 ml. of acetone and adjusting the pH to 7.0, is added in oneportion. The cooling bath is removed, and the solution is allowed towarm to room temperature over a 45 minute period with stirring. Theacetone is removed using a rotary evaporator and an equal volume ofethyl acetate is added to the aqueous layer. The pH is adjusted to 2.0,and the ethyl acetate layer is separated. The aqueous layer is extractedwith ethyl acetate (2×50 ml.) and the combined organic layers are washedwith water brine, and dried (Na₂ SO₄). Concentration in vacuo gives anoily solid, which is washed with dichloromethane and dried to give 590mg. (45% yield) of the title compound as a white solid, mp 149°-151° C.IR (KBr disc): 1785 and 1667 cm⁻¹. NMR (DMSO-d₆): 7.57 ppm (m, 1H), 6.35ppm (m, 2H), 5.77 ppm (d, 1H), 5.60 ppm (m, 2H), 5.17 ppm (s, 1H), 4.13ppm (m, 2H), 1.60 ppm (s, 3H) and 1.03 ppm (s, 3H).

EXAMPLE C6-(D-2-[N,N'-dimethylamidinothio)acetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 300 mg. of sodium iodide in 30 ml. of acetone,is added a solution of 900 mg. of6-(D-2-[2-chloroacetyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamand 0.3 ml. of triethylamine in 20 ml. of acetone. A solution of 208 mg.of N,N'-dimethylthiourea in 10 ml. of acetone is added, and then theresulting reaction mixture is heated at 55° C. for 8 hours. At thispoint, the mixture is cooled to 25° C. and the precipitate is removed byfiltration to give 390 mg. (37% yield) of the title compound, m.p.240°-250° C. IR (KBr disc): 1775 and 1667 cm⁻¹. NMR (DMSO-d₆ /D₂ O): 7.4ppm (m, 5H), 5.8 ppm (s, 1H), 5.68 ppm (m, 2H), 5.16 ppm (s, 1H), 4.2ppm (s, 2 H), 2.97 ppm (s, 6H), 1.50 ppm (s, 3H) and 0.90 ppm (s, 3H).

EXAMPLE CI

Using the procedure of Example C, but replacing theN,N'-dimethylthiourea with the appropriate reagent, the followingcompounds are prepared.

    __________________________________________________________________________     ##STR40##                                                                                    mp   Yield                                                                             IR      NMR (DMSO-d.sub.6)                              R.sup.1      (° C.)                                                                      (%) (cm.sup.-1)                                                                            (ppm)                                       __________________________________________________________________________                                   7.4 (m,5H), 5.8(s,1H), 5.61(d,1H),5.50(d,1H                                   )                                              2-(2-[pentamethyleneamidinothio]                                                              190-210                                                                            52  1770, 1667                                                                          5.1 (s,1H), 4.07 (s,2H), 3.69 (m,4H), 1.67                                    (m,4H),                                        acetamido)-2-phenylacetyl      1.55 (s,3H), 0.93 (s,3H).                      2-(2-[2-benzimidazolylthio]-                                                                  150-190                                                                            62  1770, 1667                                                                          7.36 (m,9H), 5.76 (s,1H), 5.56 (m,2H),                                        5.10 (s,1H),                                   acetamido)-2-phenylacetyl      4.15 (s,2H), 1.57 (s,3H), 0.9 (s,3H)           2-(2-[N,N'-diethylamidinothio]-                                                               172-178                                                                            88  1770, 1667                                                                          7.50 (m,5H), 5.80 (s.1H), 5.60 (m,2H),                                        5.13 (s,1H),                                   acetamido)-2-phenylacetyl      3.97 (s,2H), 3.47 (q,4H), 1.60 (s,3H),                                        1.20 (t,6H),                                                                  0.97 (s,3H)                                    2-(2-[N,N'-di-n-butylamidino-                                                                 155-170                                                                            41  1775, 1667                                                                          7.35 (m,5H), 5.80 (d,1H), 5.55 (m,2H),                                        5.05 ppm (s,1H),                               thio]acetamido)-2-phenylacetyl 4.17 (s,2H), 3.40 (m,4H), 1.56 (s,3H),                                        1.43 (m,8H),                                                                  0.96 (m,6H), 0.97 (s,3H)                       2-(2-[4-oxo-Δ.sup.2 -imidazolin-2-yl-                                                        50  1785, 1667                                                                          7.4(m,5H), 5.75(d,1H), 5.54 (m,2H), 5.10                                      (s,1H), 4.18                                   thio]acetamido)-2-phenylacetyl (s,2H), 3.93 (s,2H), 1.57 (s,3H), 0.97                                        (s,3H). -2-(2-[amidinothio]acetamido)- 177-                                   185 25 1780, 1670 7.40 (m,5H, 5.77 (d,1H),                                    5.55 (m,2H), 5.10 (s,1H),                      2-phenylacetyl                 3.90 (s,2H), 1.57 (s,3H), 0.97 (s,3H).         2-(2-[2-imidazolylthio]acet-                                                                       67        7.4 (m,5H), 7.2 (m,2H), 5.74 (s,1H), 5.63                                     (m,2H),                                        amido)-2-phenylacetyl          5.2 (s.1H), 3.89 (s,2H), 1.55 (s,3H), 0.97                                    (s,3H)                                         __________________________________________________________________________

EXAMPLE CII6-(D-2-[3-(2-[Guanylthio]acetyl)ureido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazol-5-yl)penam

To a stirred solution of 225 mg. of sodium iodide in 7.5 ml. of acetoneis added, with stirring, at 25° C., 865 mg. of6-(D-2-[3-(2-chloroacetyl)ureido]-b2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, followed by 114mg. of thiourea. Stirring is continued for 24 hours, and then theprecipitate which has formed is removed by filtration. This affords 720mg. (92% yield) of the title compound, mp 193°-211° C. (dec.). IR(KBrdisc): 1780 and 1660 cm⁻¹.

EXAMPLE CIII6-(D-2-[3-(2-[N,N'-diethylguanylthio]acetyl)ureido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

The title compound is prepared in 31.5% yield by repeating the procedureof Example CII, but using N,N'-diethylthiourea in place of thiourea.IR(KBR disc): 1780 and 1670 cm⁻¹.

EXAMPLE CIV6-(D-2-Methanesulfonamido-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

The pH of a stirred solution of 1.42 g. of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 6ml. of water and 6 ml. of tetrahydrofuran is adjusted to 7.8 (6 N sodiumhydroxide). To this solution is then added 5.70 mg. of methanesulfonylchloride, and stirring is continued for 1 hour with 6 N sodium hydroxidebeing added as necessary to maintain the pH at 7.2. At this point, thetetrahydrofuran is removed by evaporation in vacuo, and the aqueousresidue is washed with ethyl acetate. The pH is then lowered to 2.0, andthe product is extracted into ethyl acetate. The ethyl acetate is washedsuccessively with 6 N hydrochloric acid and water, and then dried usinganhydrous sodium sulfate. Evaporation of the solvent in vacuo gives thecrude product. This crude product is dissolved in the minimum amount ofethyl acetate, and then the solution is added dropwise with stirring to200 ml. of hexane. The solid which precipitates is filtered off, giving675 mg. (45%) of the title compound, m.p. 117°-48° C. IR (Nujol mull):1785 cm⁻¹ (β-lactam). NMR (in DMSO-d₆): 9.45-9.15 ppm (m, 1H), 8.05 ppm(d, 1H), 7.60-7.10 ppm (m, 5H), 5.60-5.15 ppm (m, 4H), 2.75 ppm (s, 3H),1.60 ppm (s, 3H), and 1.00 ppm (s, 3H).

EXAMPLE CV

Reaction of either6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam or6-(D-2-[2-aminoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamwith the appropriate sulfonyl chloride, according to the procedure ofExample CIV provides the following congeners:

    __________________________________________________________________________     ##STR41##                                                                                           Melting                                                                            Infrared                                                             Yield                                                                             Point*                                                                             Spectrum                                             R.sup.1         (%) (° C.)                                                                      (cm.sup.-1)                                                                           NMR Spectrum (DMSO-d.sub.6 ;ppm)          __________________________________________________________________________    2-(propanesulfonamido)-2-phenylacetyl                                                            63  100-130                                                                            1780 9.40-9.20(m,1H), 8.10 (d,1H), 7.65-7.25                                       (m,5H),                                                                       5.70-5.20(m,4H), 2.80(t,2H),                                                  1.80-1.40(m,5H),                                                              1.05-0.70(m,6H).                             2-(4-methoxybenzenesulfonamido)-                                                                 39  130-155                                                                            1790 9.25(d,1H), 8.45(d,1H), 7.70(d,2H),                                           7.50-7.10(m,5H),                             2-phenylacetyl                   7.00(d,2H), 5.60-5.15(m,4H), 3.80(s,3H),                                      1.55(s,3H),                                                                   1.00(s,3H).                                  2-(2-naphthalenesulfonamido)-2-                                                                  50   70-105                                                                            1780 9.20(d,1H), 8.80(d,1H), 8.40-7.05(m,7H),                                      5.55-5.50(m,4H),                             phenylacetyl                     1.50(s,3H), 0.95(s,3H).                      2-(2-thiophenesulfonamido)-2-                                                                    35  127-161                                                                            1790 9.30(d,1H), 8.95(d,1H), 7.90-7.00(m,8H),                                      5.70-5.20                                    phenylacetyl                     (m,4H), 1.60(s,3H), 1.00(m,6H).              2-(ethanesulfonamido)-2-phenylacetyl                                                             52  126-145                                                                            1785 9.40-9.10(m,1H), 8.10(d,1H),                                                  7.70-7.20(m,5H), 5.70-                                                        5.20(m,4H), 2.90(q,2H), 1.60(s,3H),                                           1.10(s,3H).                                  2-(4-chlorobenzenesulfonamido)-2-                                                                62  135-149                                                                            1780 9.30(d,1H), 8.90(d,1H), 7.85-7.10(m,9H),                                      5.60-5.15                                    phenylacetyl                     (m,4H), 1.60(s,3H), 1.00(s,3H).              2-(4-nitrobenzenesulfonamido)-2-                                                                 68  135-154                                                                            1790 9.35-9.10(m,2H), 8.35(d,2H), 8.00(d,2H),                                      7.50-7.10                                    phenylacetyl                     (m,5H), 5.60-5.20(m,4H), 1.60(s,3H),                                          1.00(s,3H).                                  2-(benzenesulfonamido)-2-phenylacetyl-                                                           74  133-147                                                                            1790 9.30(d,1H), 8.75(d,1H),                                                       7.90-7.05(m,10H), 5.60-5.20                                                   (m,4H), 1.60(s,3H), 1.00(s,3H).              2-(α-toluenesulfonamido)-2-phenylacetyl                                                    50  117-145                                                                            1780 9.15 -9.05(m,1H), 8.15(d,1H),                                                 7.65-7.25(m,10H), 5.70-                                                       5.20(m,4H), 1.60(s,3H), 1.05(s,3H).          2-(2-[methanesulfonamido]acetamido)-                                                             37   93-125                                                                            1780 9.50-9.25(m,1H), 8.60(d,1H),                                                  7.70-7.20(m,5H),                             2-phenylacetyl                   5.90-5.50(m,3H), 5.25(s,1H), 3.75(d,2H),                                      2.90                                                                          (s,3H), 1.60(s,3H), 1.00(s,3H).              2-(2-[benzenesulfonamido]acetamido)-                                                             56  120-144                                                                            1790 9.60-9.30(m,1H), 8.60(d,1H),                                                  8.20-7.20(m,10H),                            2-phenylacetyl                   5.80-5.50(m,3H), 5.25)s,1H), 3.60(d,2H),                                      1.60                                                                          (s,3H), 1.00(s,3H).                          2-(2-[α-toluenesulfonamido]-acetamido)-                                                    29  130-152                                                                            1780 9.60-9.30(m,1H), 8.60(d,1H),                                                  7.70-7.20(m,10H),                            2-phenylacetyl                   5.90-5.50(m,2H), 5.25(s,1H), 5.00(s,1H),                                      4.40                                                                          (s,2H), 3.70(d,2H), 1.60(s,3H),                                               1.00(s,3H).                                  2-(2-[2-thiophenesulfonamido]acet-                                                               42  128-150                                                                            1780 9.60-9.20(m,1H), 8.55(d,1H), 8.25(t,1H),                                      7.95                                         amido)-2-phenylacetyl            (d,1H), 7.70-7.19(m,7H),                                                      5.90-5.50(m,3H), 5.25                                                         (s,1H), 3.70(d,2H), 1.60(s,3H),                                               1.00(s,3H).                                  __________________________________________________________________________     *with decomposition                                                      

EXAMPLE CVI6-(D-2-[Propanesulfonamido]-2-[p-hydroxyphenyl]acetamido-)-2,2-dimethyl-3-(5-tetrazolyl)penam

The title compound is prepared in 38% yield from6-(D-2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamand propanesulfonyl chloride, using the procedure of Example CIV. Theproduct has m.p. 115°-157° C. (dec.). IR (mujol mull): 1780 cm⁻¹(β-lactam). NMR (in DMSO-d₆): 9.20-8.90 ppm (m, 1H), 7.90 ppm (d, 1H),7.30 ppm (d, 2H), 6.70 ppm (d, 2H), 5.70-5.00 ppm (m, 4H), 2.80 ppm (t,2H), 1.90-1.30 ppm (m, 5H), 1.10-0.65 ppm (m, 6H).

EXAMPLE CVII6-(D-2-[Benzenesulfonamido]-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

The title compound is prepared in 53% yield from6-(D-2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamand benzenesulfonyl chloride, using the procedure of Example CIV. Theproduct has m.p. 152°-165° C. (dec.). IR (nujol mull): 1780 cm⁻¹(β-lactam). NMR (in DMSO-d₆): 9.10 ppm (d, 1H), 8.50 ppm (d, 1H),7.90-7.40 ppm (m, 5H), 7.10 ppm (d, 2H), 6.55 ppm (d, 2H), 5.60-5.10 ppm(m, 4H), 1.55 ppm (s, 3H), 1.00 ppm (s, 3H).

EXAMPLE CVIII6-(2-D-[2-Benzamidoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 1.29 g. of6-(2-D-[2-aminoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamand 1.3 ml. of triethylamine in 15 ml. of dimethylformamide, is added0.4 ml. of benzoyl chloride. Stirring is continued for a further 30minutes, and then the reaction mixture is filtered. The filtrate isadded dropwise to 300 ml. of ether, which causes a gummy solid toprecipitate. The ether is removed by decantation, and the solid ispartitioned between ethyl acetate and water. The pH of the aqueous phaseis adjusted to 2.0 (dilute hydrochloric acid), and the ethyl acetatelayer is removed and combined with a further ethyl acetate extract ofthe acidified aqueous phase. The combined extracts are washed withwater, followed by brine, and then dried using anhydrous sodium sulfate.Evaporation of the solvent in vacuo gives a gum, which is redissolved in30 ml. of ethyl acetate, and then the solution is added dropwise to 200ml. of hexane. The white solid which precipitates is filtered off,giving 0.85 g. of the title compound, m.p. 150° C. (dec.). IR (KBrdisc): 1780 cm⁻¹ (β-lactam). NMR (DMSO-d₆): 9.40-9.20 ppm (m, 1H),8.90-8.40 ppm (m, 2H), 8.00-7.10 ppm (s, 12H), 5.90-5.40 ppm (m, 3H),5.25 ppm (s, 1H), 4.00 ppm (d, 2H), 1.60 ppm (s, 3H) and 1.00 ppm (s,3H).

EXAMPLE CIX

Following the procedure of Example CVIII, and replacing the benzoylchloride used therein by the appropriate acid chloride, the followingcongeners are produced:

    __________________________________________________________________________     ##STR42##                                                                                 Melting                                                                            Infrared                                                             Yield                                                                             Point*                                                                             Spectrum                                                      Z      (%) (° C.)                                                                      (cm.sup.-1)                                                                        NMR Spectrum DMSO-d.sub.6 (ppm)                        __________________________________________________________________________    methyl   59  135-142                                                                            1780 9.3 (d,1H), 8.6 (d,1H), 8.1 (t,1H), 7.4                                       (s,5H), 6.4-5.4 (m,9H), 5.2 (s,1H), 3.85                                      (d,2H), 1.85 (s,3H), 1.6 (s,3H), 1.0 (s,3H)            ethyl    58  148-153                                                                            1790 9.3 (d,1H), 8.5 (d,1H), 8.0 (t,1H), 7.4                                       s,5H), 5.9-5.5 (m,3H), 5.25 (s,1H), 3.8 (d,                                   2H), 2.18 (q,2H), 1.0 (s,3H), 1.18-0.8 (m,6H).         p-chlorophenyl                                                                         67  180-185                                                                            1790 9.4-9.2 (m,1H), 9.0-8.4 (m,2H), 8.0-7.2 (m,                                   9H), 5.85-5.45 (m,3H), 5.2 (s,1H), 4.0 (d,                                    2H), 1.6 (D,3H), 1.0 (s,3H).                           p-nitrophenyl                                                                          67  155-164                                                                            1780 9.6-8.0 (m,7H), 7.4 (s, 5H), 5.9-5.4 (m, 3H),                                 5.2 (s, 1H), 4.05 (d, 2H), 1.6 (s, 3H), 1.0                                   (s,3H)                                                 p-methoxyphenyl                                                                        54  151-158                                                                            1780 9.55-9.2 (m, 1H), 8.7-8.4 (m, 2H), 7.9 (d, 2H),                               7.6-7.2 (m, 5H), 5.05 (d, 2H), 5.9-5.4 (m, 3H),                               5,2 (s, 1H), 4.0 (d, 2H), 3.8 (s, 3H), 1.6                                    (s,3H),                                                                       10 (s, 3H).                                            n-propyl 60  120-132                                                                            1785 9.5-9.2 (d, 1H), 8.6-8.35 (d, 1H), 8.2-7.9 (m,                                1H),                                                                          7.45 (s, 5H), 5.9-5.9 (m,3H), 5.3 (s, 1H), 3.85                               (d,                                                                           2H), 2.3-1.95 (m, 2H), 1.8-1.3 (m, 5H), 1.1-0.75                              (m,6H)                                                 ethoxy   40  131-138                                                                            1780 9.5-9.2 (m, 1H), 8.6-8.35 (m, 1H), 7.7-7.2 (m,                                6H), 5.9-                                                                     5.5 (m, 3H), 5.25 (s, 1H), 4.2-3.6 (m, 4H), 1.6                               (s, 3H)                                                                       1.30-0.9 (m, 6H)                                       benzyloxy                                                                              65  123-128                                                                            1780 9.0-8.8 (m, 1H), 8.1 (d, 1H), 7.3 (s, 10H),                                   7.1-6.7 (m, 1H)                                                               5.9-5.45 (m, 3H), 5.15 (s, 1H), 5.1 (s, 2H), 3.85                             (d, 2H)                                                                       1.65 (s, 3H), 1.05 (s, 3H).                            __________________________________________________________________________     *with decomposition                                                      

EXAMPLE CX

Using the procedure of Example CVIII, the following compounds areprepared by the acylation of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam,6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam or6-(D-2-[3-aminopropionamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamwith the appropriate acid chloride.

    __________________________________________________________________________     ##STR43##                                                                                    Yield                                                                             IR  NMR (DMSO-d.sub.6)                                      R.sup.1       (%) (cm.sup.-1)                                                                       (ppm)                                                 __________________________________________________________________________    2-(phenylthio)acetyl                                                                          31  1780                                                                              1.10 (s,3H), 1.70 (s,3H), 3.85 (s,2H), 5.25-5.80                              (m,3H),                                                                       7.10-7.50 (m,6H), 9.10 (d,1H)                         D-2-(2-[phenylthio]acet-                                                                      22  1785                                                                              1.05 (s,3H), 1.60 (s,3H), 3.80 (s,2H), 5.10-6.00                              (m,5H)                                                amido)-2-phenylacetyl   7.10-7.60 (m,10H), 8.8-9.10 (m,1H), 9.30-9.60                                 (m,1H)                                                2-(ethylthio)acetyl                                                                           45  1785                                                                              0.80-1.30 (m,6H), 1.60 (s,3H), 2.30-2.80 (m.2H +                              DMSO),                                                                        3.20 (s,2H), 5.10-6.10 (m,4H), 8.8 (d,1H)             D-2-(2-[ethylthio]acet-                                                                       59  1785                                                                              0.80-1.30 (m,6H), 1.55 (s,3H), 2.30-2.80 (m,2H +                              DMSO),                                                amido)-2-phenylacetyl   3.20 (s,2H), 5.10-5.80 (m,4H), 6.00-7.00 (m,1H),                              7.10-                                                                         7.60 (m,5H), 8.60 (d,1H), 9.10-9.50 (m,1H)            3-(methoxycarbonyl)-                                                                          46  1785                                                                              1.05 (s,3H), 1.50-2.05 (m,5H), 2.10-2.65 (m,4H +                              DMSO),                                                butyryl                 3.60 (s,3H), 5.20-6.00 (m,4H), 8.90 (d,1H)            D-2-(3-[methoxycarbonyl]-                                                                     68  1790                                                                              0.80-1.40 (m,5H), 1.50-2.10 (m,5H), 2.20-2.80                                 (m,2H + DMSO),                                        butyramido)-2-phenylacetyl                                                                            3.65 (2,3H), 5.20-5.80 (m,4H), 7.20-7.60 (m,5H),                              8.60 (d,1H),                                                                  9.20-9.50 (m,1H)                                      2-(ethoxycarbonyl)acetyl                                                                      31  1785                                                                              0.80-1.40 (m,6H), 1.65 (s,3H), 3.40 (s,2H), 4.10                              (q,2H),                                                                       5.20-5.75 (m,4H), 9.10 (d,1H)                         D-2-(2-[ethoxycarbonyl)-                                                                      31  1775                                                                              0.90-1.40 (m, 6H), 1.65 (s,3H), 3.45 (s,2H), 4.20                             (q,2H),                                               acetamido)-2-phenyl acetyl                                                                            4.40-6.00 (m,H.sub.2 O+5H), 5.72-7.75(m,5H), 9.00                             (d,1H), 9.30-                                                                 9.70 (m,1H)                                           2-(benzylthio)acetyl                                                                          41  1780                                                                              1.05 (s,3H), 1.70 (s,3H), 3.20 (s,2H), 3.85                                   (s,2H),                                                                       5.25-5.80 (m,3H), 7.20-7.50 (m,6H), 8.95 (d,1H)       D-2-(2-[benzylthio]acet-                                                                      39  1780                                                                              1.00 (s,3H), 1.60 (s,3H), 3.25 (s,2H), 3.80                                   (s,2H),                                               amido)-2-phenylacetyl   5.20-5.90 (m,4H), 7.00-7.80 (m,11H), 8.80 (d,1H),                             9.30-                                                                         9.70 (m,1H)                                           D-2-(3-benzamido)-                                                                            43  1780                                                                              1.05 (s,3H), 1.6 (s,3H), 2.3-2.8 (m,2H), 3.2-3.8                              (2H,m)                                                propionamido)-2-phenyl- 5.3 (s,1H), 5.4-6.0 (m,3H), 7.1-7.65 (m,10H),                                 7.7-8.0                                               acetyl                  (m,1H), 8.3-8.9(m,2H), 9.2-9.5 (m,1H)                 D-2-(3-[4-chlorobenzam-                                                                       63  1785                                                                              1.05 (s,3H), 1.6 (s,3H), 2.3-2.8 (m,2H), 3.0-3.8                              (m,2H),                                               ido]propionamido)-2-phenyl-                                                                           5.25 (s,1H), 5.45-5.95 (m,3H), 7.0-8.1 (m,10H),                               8.35-8.8                                              acetyl                  (m,2H), 9.1-9.45 (broad hump 1H)                      D-2-(3-[3-chlorobenzam-                                                                       57  1785                                                                              1.05 (s,2H), 1.6 (s,3H), 2.25-2.7 (m,2H), 3.2-3.7                             (m,2H)                                                ido]propionamido)-2-phenyl-                                                                           5.25 (m,1H), 5.45-5.9 (m,3H), 7.2-8.0 (m,9H),                                 8.45-8.8                                              acetyl                  (m,2H), 9.2 (d,1H)                                    D-2-(3-[2-furnancarboxamido]-                                                                 34  1780                                                                              1.05 (s,3H), 1.6 (s,3H), 2.2-2.7 (m,2H), 3.1-3.7                              (m broad2-H)                                          propionamido)-2-phenylacetyl                                                                          5.25 (s,1H), 5.4-5.95 (m,3H), 6.55-6.7 (m,1H),                                7.0-7.75                                                                      (G,7H), 7.8 (s,1H), 8.1-8.4 (m,1H), 8.65 (d,1H),                              9.05-9.35                                                                     (m,1H)                                                D-2-(3-acetamidopropionamido)-                                                                33  1780                                                                              1.05 (s,3H), 1.65 (s,3H), 2.2-2.65 (m,3H),                                    3.1-3.6 (m,2H),                                       2-phenylacetyl          5.25 (s,1H), 5.4-6.0 (m,3H), 7.2-7.7 (m,5H),                                  7.7-8.0 (m,1H),                                                               8.6 (s,1H), 9.2 (d,1H)                                __________________________________________________________________________

EXAMPLE CXI

Reaction of the appropriate6-(2-substituted-2-aminoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam or6-(2-substituted-2-[2-aminoacetamido]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamwith the requisite acid chloride, according to the procedure of ExampleCVIII, affords the following congeners:

    ______________________________________                                         ##STR44##                                                                      R.sup.7         m        Z                                                  ______________________________________                                        isopropyl         0      methyl                                               isopropyl         0      phenyl                                               isopropyl         0      p-chlorophenyl                                       isopropyl         0      2-thienyl                                            phenyl            0      propyl                                               phenyl            0      isobutyl                                             phenyl            0      n-hexyl                                              phenyl            0      m-tolyl                                              phenyl            0      p-methoxyphenyl                                      p-hydroxyphenyl   0      p-bromophenyl                                        p-hydroxyphenyl   0      2-furyl                                              m-methoxyphenyl   0      4-pyridyl                                            o-tolyl           0      p-fluorophenyl                                       m-bromophenyl     0      3,4-dichlorophenyl                                   2-thienyl         0      p-n-hexyloxyphenyl                                   3-thienyl         0      phenyl                                               2-furyl           0      3-thienyl                                            p-(hydroxymethyl)phenyl                                                                         0      2-furyl                                              phenyl            1      n-butyl                                              phenyl            1      2-pyridyl                                            phenyl            1      m-bromophenyl                                        p-hydroxyphenyl   1      2-thienyl                                            p-hydroxyphenyl   1      methyl                                               ______________________________________                                    

EXAMPLE CXII6-(2-[3-Phenylureido]-2-[p-hydroxphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 0.78 g. (0.002 mole) of6-(2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamin 40 ml. of 1:1 acetone-water, the pH of which has been adjusted to 6.0by the addition of sodium bicarbonate solution, is added 0.238 g. (0.002mole) of phenyl isocyanate, at ambient temperature. Stirring iscontinued at ambient temperature for a further 30 minutes, and then 50ml. of ethyl acetate is added. The pH of the aqueous phase is lowered to1.5 with 1 N hydrochloric acid, and then the organic layer is removed,dried and evaporated to dryness in vacuo. The residue is re-dissolved ina small volume of ethanol, to which 0.2 ml. of triethylamine is thenadded. The resulting solution is added dropwise to 200 ml. of ether,with vigorous stirring, and then the solid which precipitates isfiltered off. This affords 0.8 g. (66% yield) of6-(2-[3-phenylureido]-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as its triethylamine salt,m.p. 165°-170° C. (dec.). The infrared spectrum of the product (KBrdisc) shows absorptions at 1790 cm⁻¹ (β-lactam) and 1670 cm⁻¹ (amide I).The NMR spectrum (DMSO-d₆ /D₂ O) shows absorptions at 7.60-6.70 ppm(multiplet, 9H, aromatic hydrogens), 5.80-5.50 ppm (multiplet, 3H, C-5and C-6 hydrogens, and side-chain methine hydrogen), 5.05 ppm (singlet,1H, C-3 hydrogen), 3.05 ppm (quartet, 6H, N--CH₂ CH₃), 1.55 ppm(singlet, 3H, C-2 methyl hydrogen), 1.10 ppm (triplet, 9H, N-CH₂ CH₃)and 0.95 ppm (singlet, 3H, C-2 methyl hydrogens).

The MIC of the title compound against Strep. pyogenes is <0.1 μg./ml.

EXAMPLE CXIII

Using the procedure of Example CXII, and reacting either6-(2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam or6-(2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamwith the appropriate isocyanate, the following compounds are prepared.The compounds are isolated as their triethylamine salts.

    __________________________________________________________________________     ##STR45##                                                                                      Yield                                                                             m.p.                                                                              Infrared Spectrum                                   R.sup.7                                                                              Q          (%) (° C.)                                                                      (cm.sup.-1)                                                                            NMR Spectrum (DMSO-d.sub.6 /D.sub.2                                           O; ppm)                                   __________________________________________________________________________    C.sub.6 H.sub.5                                                                     p-CH.sub.3 OC.sub.6 H.sub.4 NHCONH                                                        64  148-52                                                                            1785, 1670, 1615,                                                                       7.65-7.15(m,7H), 6.85(d,2H),                                                  5.75-5.40(m,3H)                                                     1550, 1515                                                                              5.05(s,1H), 3.7(s,3H), 3.05(q,6H),                                            1.55(s,                                                                       3H), 1.15(t,9H), 0.95(s,3H).              C.sub.6 H.sub.5                                                                     p-ClC.sub.6 H.sub.4 NHCONH                                                                75  148-55                                                                            1785, 1680, 1660,                                                                       7.75-7.20(m,9H), 5.85-5.45(m,3H),                                             5.05(s,1H),                                                         1550, 1495                                                                              3.05 (q,6H), 1.55(s,3H), 1.15(t,9H),                                          0.95(s,3H).                               C.sub.6 H.sub.5                                                                     p-CH.sub.3 C.sub.6 H.sub.4 NHCONH                                                         79  152-55                                                                            1785, 1680, 1615,                                                                       7.60-6.95(m,9H), 5.80-5.50(m,3H),                                             5.10(s,1H),                                                         1550, 1505                                                                              3.05(q,6H), 2.15(s,3H), 1.60(s,3H),                                           1.10(t,                                                                       9H, 0.95(s,3H).                           C.sub.6 H.sub.5                                                                     C.sub.6 H.sub.5 HNCONH                                                                    79  150-55                                                                            1785, 1670, 1600,                                                                       7.75-6.85(m,10H), 5.80-5.45(m,3H),                                            5.10(s,1H),                                                         1550, 1505                                                                              3.10(q,6H), 1.60(s,3H), 1.15(t,9H),                                           0.95(s,3H),                               C.sub.6 H.sub.5                                                                     CH.sub.3 NHCONH                                                                           45  112-20                                                                            1785, 1655, 1565,                                                                       7,45(s,5H), 5.70-5.40(m,3H),                                                  5.1(s,1H), 3.1(q,                                                   1505      6H), 2.60(d,3H), 1.60(s,3H),                                                  1.20(t,9H), 0.95                                                              (s,3H).                                   p-HOC.sub.6 H.sub.4                                                                 p-CH.sub.3 OC.sub.6 H.sub.4 NHCONH                                                        63  1785, 1670, 1655,                                                                 7.60-7.20(m,4H), 7.55-6.75(m,4H), 5.85-5.40(m,                                1615, 1550, 1515                                                                        3H), 5.05(s,1H), 3.70(s,3H),                                                  3.10(q,6H), 1.60                                                              (s,3H), 1.20(t,9H), 0.95(s,3H).           p-HOC.sub.6 H.sub.4                                                                 p-ClC.sub.6 H.sub.4 NHCONH                                                                39  170 1785, 1680, 1600,                                                                       7.65-6.75(m,8H), 5.75-5.45(m,3H),                                             5.05(s,1H),                                                         1550, 1520, 1505                                                                        3,10(q,6H), 1.55(s,3H), 1.15(t,9H),                                           0.95(s,3H).                               __________________________________________________________________________

EXAMPLE CXIV6-(2-[3-(2-[p-Chlorophenyl]acetimidoyl)ureido]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 480 mg. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam and 404 mg. of triethylamine,in 6 ml. of N,N-dimethylformamide, is added 650 mg. of2-(3-[2-(p-chlorophenyl)acetimidoyl]ureido)acetyl chloridehydrochloride. Stirring is continued for 1 hour, and then the reactionmixture is filtered. The filtrate is added to 300 ml. of ether, and thesolid which precipitates is filtered off. The solid is washed thoroughlywith methylene chloride, and dried, giving 585 mg. of the titlecompound, m.p. 150°-162° C. IR spectrum (Nujol mull): 1780 cm⁻¹(β-lactam). NMR spectrum (DMSO-d₆): 8.90 ppm (d, 1H), 8.00-7.20 ppm (m,8H), 5.80-5.20 ppm (m, 3H), 4.10-3.60 ppm (m, 4H), 1.65 ppm (s, 3H),1.10 ppm (s, 3H).

EXAMPLE CXV

Using the procedure of Example CXIV and reacting either6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam or6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam withthe appropriate acid chloride hydrochloride the following compounds areproduced.

    __________________________________________________________________________     ##STR46##                                                                                      Melting                                                                            Infrared                                                             Yield                                                                             Point*                                                                             Spectrum                                                R.sup.1      (%) (° C.)                                                                      (cm.sup.-1)                                                                        NMR Spectrum (DMSO-d.sub.6 ;                      __________________________________________________________________________                                ppm)                                              2-(3-[benzimidoyl]ureido)-                                                                  81  153-164                                                                            1780 8.90(d,1H), 8.70-7.20(m,9H),                                                  5.80-5.20(m,3H),                                  acetyl                      4.10-3.70(m,2H), 1.65(s,3H), 1.10(s,3H).          2-(3-[p-methoxybenzimidoyl]-                                                                71  162-168                                                                            1775 8.80(d,1H), 8.05-6.20(m,8H), 5.75-                                            5.15(m,3H),                                       ureido)acetyl               4.05-3.70(m,5H), 1.65(s,3H), 1.05(s,3H).          2-(2-[3-(2-[p-chlorophenyl]-                                                                50  160-169                                                                            1780 9.40-9.20(m,1H), 8.80(d,1H),                                                  8.40-7.10(m,13H),                                 acetimidoyl)ureido]acet-    5.90-5.15(m,4H), 4.05-3.70(m,4H),                                             1.55(s,3H),                                       amido)-2-phenylacetyl       1.00(s,3H).                                       2-(2-[3-(benzimidoyl)ureido]-                                                               45  160-166                                                                            1775 9.40(d,1H), 8.60(d,1H), 8.10-6.00(m,14H),                                     5.90-                                             acetamido)-2-phenylacetyl   5.10(m,4H), 4.00-3.60(m,2H), 1.55(s,3H),                                      1.00                                                                          (s,3H).                                           2-(2-[3-(p-methoxybenzimi-                                                                  64  168-174                                                                            1775 9.40(d,1H), 8.70(d,1H), 8.10-6.30(m,13H),                                     6.00-                                             doyl)ureido]acetamido-2-    5.10(m,4H), 4.10-3.70(m,5H), 1.55(s,3H),                                      1.00                                              phenylacetyl                (s,3H).                                           __________________________________________________________________________

EXAMPLE CXVI 6-(3-Phenylureido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred slurry of 724 mg. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 10 ml. of methylenechloride is added 1.3 ml. of triethylamine. The mixture is stirred for40 minutes, and then filtered. To the filtrate is added 0.35 ml. ofphenyl isocyanate. Stirring is continued for a further 45 minutes, andthen the reaction mixture is cooled in an ice-bath for 30 l minutes. Thesolid which precipitates is filtered off, washed with ether, and dried,giving 935 mg. of the title compound as its triethylamine salt, m.p.110°-120° C. IR spectrum (Nujol mull): 1775 cm⁻¹ (β-lactam), 1700 cm⁻¹,1600 cm⁻¹ and 1550 cm⁻¹. NMR spectrum (DMSO-d₆): 9.00 ppm (s, 1H),7.50-6.70 ppm (m, 7H), 5.65 ppm (m, 2H), 5.10 ppm (s, 1H), 3.10 ppm (q,6H), 1.80 ppm (s, 3H), 1.18 ppm (t, 9H), 1.00 ppm (s, 3H).

In like manner, using ethyl isocyanate, there is obtained a 70% yield of6-(3-ethylureido)-2,2-dimethyl-3-(5-tetrazolyl)penam triethylamine salt,m.p. 80°-90° C. IR spectrum (KBr disc): 1785 cm⁻¹ (β-lactam), 1668 cm⁻¹and 1570 cm⁻¹. NMR spectrum (DMSO-d₆): 7.80 ppm (m, 1H), 6.50 ppm (m,2H), 5.60 ppm (m, 2H), 5.10 ppm (s, 1H), 3.10 ppm (q, 8H), 1.60 ppm (s,3H), 1.40-0.70 ppm (m, 15H).

EXAMPLE CXVII6-(D-2-Allophanamido-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 1.12 g. (3 mmole) of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and0.485 ml. of triethylamine in 6 ml. of water is added portionwise,during 10 minutes, 0.512 g. (3.5 mmole) of N-methyl-N-nitrosobiuret.Stirring is continued for a further 2 hours, and then the pH is adjustedto 2.0. The product is extracted into ethyl acetate, and then theextract is treated with 0.42 ml. (3.0 mmole) of triethylamine and thenevaporated to dryness in vacuo. This affords 1.4 g. (84% yield) of thetitle compound as its triethylamine salt. IR (KBr disc): 1785, 1695 and1540 cm⁻¹. NMR (in CDCl₃): 9.4-8.4 ppm (m), 8.3 ppm (s), 7.7-7.1 ppm(m), 7.1-6.7 ppm (m), 5.9-5.3 ppm (m), 5.3-5.0 ppm (d), 4.5-4.1 ppm (d),1.6 ppm (s), 1.0 ppm (s).

EXAMPLE CXVIII 6-(3-Aminomethyl-2-phenylisocrotonamido)-2,2-dimethyl-3l-(5-tetrazolyl)penam

To a stirred solution of 720 mg. (3 mmole) of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam and 0.84 ml. (6 mmole) oftriethylamine is 15 ml. of methylene chloride, at -20° C., is added 706mg. (3 mmole) of 3-azidomethyl-2-phenylisocrotonoyl chloride (TheJournal of Antibiotics, Tokyo, 24, 626 [1971]) dissolved in 5 ml. ofmethylene chloride. The cooling is removed, and the reaction mixture isstirred as it warms to room temperature and then for a further 15minutes. The pH of the reaction mixture is then adjusted to 7.8, and itis extracted with ethyl acetate. The ethyl acetate is discarded, and thepH of the residual aqueous phase is lowered to 2.5. It is thenre-extracted with ethyl acetate, and to this second extract is added 3mmoles of sodium 2-ethylhexanoate. The solvent is then removed byevaporation in vacuo leaving a gummy solid (1.12 g.).

The above solid is dissolved in 35 ml. of water, and 500 mg. of 10%palladium-on-carbon is added. The mixture is then hydrogenated in a Parrhydrogenator, under 20 p.s.i. pressure, at 25° C., for 16 hours. At thispoint, the catalyst is removed by filtration, and the filtrate isacidified to pH 2.0. It is filtered, and the pH of the filtrate israised to 5.7. The filtrate is lyophilized, to produce 900 mg. (87%yield) of the title compound. IR (KBr disc): 1770 cm⁻¹ (β-lactam).

EXAMPLE CXIX6-(D-2-[2-(Benzamidino)acetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

A mixture of 1.72 of g. of6-(D-2-[2-aminoacetamido]-2-phenylacetamido-2,2-dimethyl-3-(5-tetrazolylbenam,0.66 g. of ethyl benzimidate and 20 ml. of N,N-dimethylformamide isstirred for 1 hour at 25° C. The filtered reaction mixture is then addeddropwise with stirring to a large excess of chloroform, and the solidwhich precipitates is filtered off. This affords 0.93 g. (43% yield) ofthe title compound, m.p. 198° C. (dec.). IR (KBr disc): 1770 cm⁻¹(β-lactam). NMR (DMSO-d₆): 9.35-9.00 ppm (m, 2H), 8.00-7.15 (m, 12H),5.95 ppm (d, 2H), 5.55. 5.30 ppm (m, 2H), 5.00 ppm (s, 1H), 4.35 ppm (s,2H), 1.50 ppm (s, 3H) and 0.90 ppm (s, 3H).

EXAMPLE CXX

Following the procedure of Example CXIX, and reacting6-(D-2-[2-aminoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamwith the appropriate imidate ester, the following compounds areprepared:

    __________________________________________________________________________     ##STR47##                                                                                    Melting                                                                            Infrared                                                             Yield                                                                             Point*                                                                             Spectrum                                                 Z           (%) (° C.)                                                                      (cm.sup.-1)                                                                        NMR Spectrum (DMSO-d.sub.6 ; ppm)                   __________________________________________________________________________    4-pyridinecarbox-                                                                         60  193  1770 9.1-8.7(m,4H), 7.9-7.2(m,7H), 6.4-4.7(m,11H),                                 4.3(s,2H),                                          amidomethyl               1.5(s,3H), 0.9(s,3H).                               3,5-dibromobenzami-                                                                       32  195  1775 9.3-8.8(m,2H), 8.2-7.1(m,8H), 5.95-5.3(m,3H),                                 4.95(s,1H),                                         dinomethyl                4.24(s,2H), 1.5(s,3H), 0.9(s,3H).                   2-thiopnenecarboxam-                                                                      35  185  1770 9.45-8.9(m,2H), 8.15-7.9(m,2H), 7.7-7.2(m, 6H),                               6.0-5.4(m,                                          indinomethyl              3H), 5.05(s,1H), 4.22(s,2H), 1.5(s,3H),                                       0.9(s,3H).                                          acetamidinomethyl                                                                         69  185  1775 9.6-8.6(m,5H), 7.75-7.15(m,5H), 6.0-5.3(m,3H),                                5.0(s,1H),                                                                    4.14(s,2H), 2.22(s,3H), 1.55(s,3H),                                           0.92(s,3H).                                         4-pyridinecarboxami-                                                                      22  200  1775 9.7-9.3(m,2H), 8.42(d,2H), 7.8(d,2H),                                         7.2(s,5H), 6.0-5.3                                  dinomethyl N-oxide        (m,3H), 5.05(s,1H), 4.2(s,2H), 1.55(s,3H),                                    0.95(s,3H).                                         (2-[p-chlorophenyl]-                                                                      45  192  1770 9.8-8.7(m,4H), 7.7-7.1(m,10H), 5.9-5.2(m,3H),                                 4.95(s,1H),                                         acetamidino)methyl        4.4-3.0(m,6H), 1.5(s,3H), 0.9(s,3H).                p-nitrobenzamidino-                                                                       82  197  1770 9.4-8.9(m,2H), 8.5(d,2H), 8.1(d,2H),                                          8.0-6.6(m,8H), 5.9(d,                               methyl                    1H), 5.65-5.4(m,2H), 5.05(s,1H), 4.35(s,2H),                                  1.55(s,3H),                                                                   0.9(s,3H).                                          m-sulfamoylbenz-                                                                          51  180-185                                                                            1780 8.35-7.5(m,9H), 5.85(d,2H), 5.55(m,2H),                                       5.02(s,1H), 4.35                                    amidinomethyl             (m,2H), 1.50(s,3H), 0.95(s,3H).                     m-cyanobenzamidino-                                                                       75  180-185                                                                            1785 8.4-7.45(m,9H), 5.85(d,1H), 5.5(m,2H),                                        5.02(s,1H), 4.3(m,                                  methyl                    2H), 1.5(s,3H), 0.9(s,3H).                          2-benzimidazolecarbox-                                                                    59  126-140                                                                            1785 8.0-7.2(m,9H), 5.9(d,1H), 5.55(mm2H),                                         5.0(s,1H), 4.1(s,2H),                               amidinomethyl (tri-       3.0(q,6H), 1.5(s,3H), 1.18(t,9H), 0.9(s,3H).        ethylamine salt)                                                              2-pyrimidinecarbox-                                                                       49  149-169                                                                            1785 9.3(s,1H), 8.85(m,2H), 7.35(m,5H), 5.8(d,1H),                                 5.5(m,2H),                                          amidinomethyl             5.03(s,1H), 4.25(m,2H), 1.5(s,3H), 0.9(s,3H).       3-cyano-5-iodobenz-                                                                       58       1780 8.55(m,3H), 7.6(m,5H), 5.9(d,1H), 5.6(m,3H),                                  5.03(s,1H),                                         amidinomethyl             4.2(m,2H, 1.55(s,3H), 0.9(s,3H).                    2-quinoxalinecarbox-                                                                      53       1785 9.8(s,1H), 8.2(m,4H), 7.5(m,5H), 5.95(d,1H),                                  5.6(m,2H),                                          amidonomethyl             5.1(s,1H), 4.3(m,2H), 1.55(s,3H), 0.95(s,3H).       m-carbamoylbenzamidi-                                                                     81       1785 8.6-7.25(m,9H), 5.95(d,1H), 5.56(m,2H),                                       5.05(s,1H),                                         nomethyl                  4.4(m,2H), 1.55(s,3H), 0.9(s,3H).                   2-pyrrolecarboxamidi-                                                                     83       1785 7.3(m,7H), 6.3(m,1H), 5.85(d,1H), 5.5(m,2H),                                  5.0(s,1H),                                          nomethyl                  4.25(m,2H), 1.55(s,3H), 0.9(s,3H).                  2-benzthiazolecarb-                                                                       54  212-15                                                                             1770 0.95 (s,3H), 1.55(s,3H), 3.95(b,2H), 5,1                                      (s,1H), 5.4-                                        oxamidinomethyl      1667 5.95 (c,3H), 7.5 (b,7H), 8.2 (b,2H)                 3,5-disulfamoyl-                                                                          31  185-92                                                                             1770 0.95 (s,3H), 1.55 (s,3H), 4.1 (b,2H), 5.1                                     (s,1H), 5.45-                                       benzamidinomethyl    1667 5.95 (c,3H), 7.5 (b,5H), 8.5 (b,3H)                 3-sulfamoyl-5-bromo-                                                                      78  196-200                                                                            1786 0.95 (s,3H), 1.55 (s,3H), 4.25 (b,2H), 5.1                                    (s,1H), 5.6 (c,2H),                                 benzamidinomethyl    1681 5.85 (s,1H), 7.5 (b,5H), 8.1 (b,2H), 8.6                                      (b,1H)                                              3-sulfamoyl-5-chloro-                                                                     71  197-200                                                                            1770 0.95 (s,3H), 1.55 (s,3H), 4.4 (b,2H), 5.05                                    (s,1H), 5.55                                        benzamidinomethyl    1667 (c,2H), 5.8 (s,1H), 7.5 (b,5H), 8.0 (6,2H), 8.4                               (b,1H)                                              3-chloro-5-cyano-    1786 0.95 (s,3H), 1.55 (s,3H), 4.25 (b,2H), 5.05                                   (s,1H), 5.5                                         benzamidinomethyl                                                                         73  203  1681 (c,2H), 5.85 (s,1H), 7.4 (b,5H), 8.25 (b,3H)        2-benzoxazolecar-                                                                         73  199  1786 0.95 (s,3H), 1.55 (s,3H), 4.3 (b,2H), 5,.1                                    (s,1H), 5.55                                        boxamidinomethyl     1667 (c,2H), 5.8 (s,1H), 7.2-8.2 (c,9H)                  __________________________________________________________________________     *with decomposition                                                      

EXAMPLE CXXI

Reaction of the appropriate compound of formula I or II, wherein R² andR³ are each hydrogen and R¹ is of formula V, wherein n is 1 and Q isamino, with the requisite ethyl imidate, according to the procedure ofExample CXIX, produces the following compounds

    __________________________________________________________________________     ##STR48##                                                                                   Melting                                                                            Infrared                                                             Yield                                                                             Point*                                                                             Spectrum                                                  R.sup.1    %   (0° C.)                                                                     (cm.sup.-1)                                                                        NMR Spectrum (DMSO-d.sub.6 /D.sub.2 O;               __________________________________________________________________________                             ppm)                                                 2-(3,5-dimethylbenz-                                                                     31  170-186                                                                            1775 7.35 (s, 3H), 5.77 (d, 1H), 5.60 (d,                 amidino)acetyl           1H), 5.20 (s, 1H), 4.34 (s, 2H) 2.37                                          (s, 6H), 1.67 (s, 3H), 1.01 (s, 3H).                 2-(4-pyridinecarbox-                                                                     24  170-182                                                                            1785,1680                                                                          8.40 (d, 2H), 7.70 (d, 1H), 5.83 (d,                 amidino)acetyl           1H), 5.67 (d, 1H),5.30 (s, 1H), 4.50                                          (s, 2H), 1.67 (s, 3H) 1.01 (s, 3H).                  2-(acetamidinoacetyl)                                                                    69  118-127                                                                            1770,1680                                                                          5.83 (d, 1H), 5.67 (d, 1H), 5.30                                              (s, 1H), 4.33 (s, 2H), 2.40 (s, 3H),                                          1.67 (s, 3H), 1.01 (s, 3H).                          2-(2-thiophenecarbox-                                                                    67  175-180                                                                            1780 8.03 (m, 2H), 7.34 (m, 1H), 5.78 (d,                 amidino)acetyl           1H), 5.60 (d, 1H) 5.19 (s, 1H), 4.35                                          (s, 2H), 1.67 (s, 3H), 1.01 (s, 3H)                  2-(4-pyridiencarbox-                                                                     58  172  1780,1680                                                 amidino)-3-phenyl-                                                            propionyl                                                                     2-(4-pyridinecarbox-                                                                     38       1785,1680                                                                          8.40 (d, 2H), 7.77 (d, 2H), 5.76 (d,                 amidino)-3-methyl-       1H), 5.56 (d, 1H) 5.19 (s, 1H), 4.33                 butyryl                  m, 1H), 2.30 (m, 1H), 1.60 (s, 3H)                                            1.01 (s, 3H).                                        __________________________________________________________________________     *decomposition                                                           

EXAMPLE CXXII

Using the procedure of Example CXIX, and reacting6-(D-2-[3-aminopropionamido]-2-phenylacetamido)-2,2-dimethyl-3(5-tetrazolyl)penamwith the appropriate ethyl imidate, the following compounds areprepared:

    __________________________________________________________________________     ##STR49##                                                                                       Yield                                                                              IR                                                      R.sup.1          (%)  (cm.sup.-1)                                                                        NMR(DMSO-d.sub.6) (ppm)                          __________________________________________________________________________    D-2-(3-[4-pyridinecar                                                                            63   1765 0.9 (s,3H), 1.55 (s,3H), 2.5-3.0 (m,2H),                                      3.45-4.0 (m,2H),                                 boxamidino]propionam-        5.0 (s,1H), 5.3-5.6 (m,2H), 5.85 (s,1H),                                      7.0-8.0 (m,11H),                                 ido)-2-phenylacetyl          8.6-9.3 (m,4H)                                   D-2-(3-pyridine-1-oxide-                                                                         82   1770 DMSO-D.sub.6 :δ0.9 (s,3H), 1.55                                         (s,3H),2.4-3.0 (m,2H), 3.35-3.9                  4-carboxamidino]pro-         (m,2H), 5.05 (s,1H), 5.35-5.65 (m,2H), 5.85                                   (d,1H), 6.4-8.1                                  pionamido)-2-phenylacetyl    (m,12H), 8.45(d,2H), 8.7-9.1 (m,2H).                                          DMSO-D.sub.6 +D.sub.20 : δ0.95 (s,3H),                                  1.5(s,3H), 2.4-3.0 (m,2H), 3.4-                                               4.0(m,2H), 5.1 (s,1H), 7.45 (s,5H), 7.8                                       (d,2H), 8.45 (d,2H)                              D-2-(3-[2-thienylcarb-                                                                           78   1775 DMSO-D.sub.6 :δ0.95 (s,3H), 1.55                                        (s,3H), 2.4-3.0 (m,2H), 3.4-4.0                  oxamidino]propionam-         (m,2H), 5.05 (s,1H), 5.25- 5.65 (m,2H), 5.85                                  (d,1H), 7.1-7.65                                 ido)-2-phenylacetyl          m7-8H), 7.9-8.25 (m,2H), 7.0-9.7 (Broad &                                     m4-5H)                                                                        DMSO D.sub.6 +D.sub.20 :δ0.95 (s,3H),                                   1.55 (s,3H), 2.4-3.0 (m,2H), 3.5-                                             4.05 (m,2H), 5.2 (s,1H), 5.45-5.9 (m,3H),                                     7.2-7.7 (m,6H), 7.8-                                                          8.25 (m,2H)                                      D-2-(3-benzamidino-                                                                              74   1765 DMSO-D.sub.6 :δ0.9 (s,3H), 1.55                                         (s,3H), 2.4-2.95 (m,2H), 3.3-3.9                 propionamido)-2-             (m,2H), 5.05 (s,1H), 5.3-5.6 (m,2H), 5.85                                     (d,1H), 7.2-8.0                                  phenylacetyl                 (11H) 8.6-10.0 (4-5H)                            D-2-(3-[3,5-dibromobenzam-                                                                       82   1770 1.5 (s,3H), 2.45-2.9(m,2H), 3.3-3.8(m,2H),                                    4.95 (s,1H), 5.3-                                idino]propionamido)-2-       5.5 (m,2H), 5.8 (d,1H), 7.1-7.7 (m6-7H);                                      7.8-8.3 (m,3H),                                  phenylacetyl                 8.8-9.3 (m,2H)                                   D-2-(3-acetamidinopropionamido)-                                                                 70   1770 0.95 (s,3H), 1.55 (s,3H), 2.15 (s,3H),                                        2.25-2.8 (m,2H),                                 2-phenylacetyl               3.1-3.7 (m,2H), 5.05 (s,1H), 5.3-5.65                                         (m,2H), 5.85 (d,1H), 7.0-                                                     7.7 (m,5H), 8.0-10.0 (5-6H)                      D-2-(3-[3,4-dichlorobenz-                                                                        81   1770 0.95 (s,3H), 1.55 (s,3H), 2.5-3.0 (m,2H)         amidino]propionamido)-2-phenyl-                                                                            3.35-3.9 (m,2H), 5.0 (s,1H), 5.25-5.65                                        (m,2H),                                          acetyl                       5.85 (d,1H), 6.8-9.4 (m, 12-13H),                D-2-(3-[4-chlorophenyl]acet-                                                                     86   1700 0.95 (s,3H), 1.55 (s,3H), 2.4-2.9 (m,2H),                                     3,2-4.0                                          amidinopropionamido)-2-      m,4H), 5.05 (s,1H), 5.8 (d,1H), 7.1-7.7                                       (m,10H).                                         phenylacetyl                                                                  __________________________________________________________________________

EXAMPLE CXXIII

Reaction of the appropriate6-(2-substituted-2-aminoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam or6-(2-substituted-2-[2-aminoacetamido]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamwith the appropriate imidate ester, according to the procedure ofExample CXIX produces the following congeners:

    ______________________________________                                         ##STR50##                                                                    R.sup.7        m     Z                                                        ______________________________________                                        methyl         0     acetamidinomethyl                                        methyl         0     benzamidinomethyl                                        methyl         0     p-chlorobenzamidinomethyl                                isopropyl      0     m-bromobenzamidinomethyl                                 isopropyl      0     p-methoxybenzamidinomethyl                               isopropyl      0     3,5-dichlorobenzamidinomethyl                            isopropyl      0     2-furancarboxamidinomethyl                               isopropyl      0     4-pyridinecarboxamidinomethyl                            phenyl         0     m-methoxybenzamidinomethyl                               phenyl         0     p-fluorobenzamidinomethyl                                phenyl         0     p-methylbenzamidinomethyl                                phenyl         0     m-methylthiobenzamidinomethyl                            p-hydroxyphenyl                                                                              0     2-benzimidazolecarboxamidino-                                                 methyl                                                   p-hydroxyphenyl                                                                              0     benzamidinomethyl                                        p-(hydroxymethyl)phenyl                                                                      0     benzamidinomethyl                                        2-thienyl      0     4-pyridinecarboxamidinomethyl                            2-thienyl      0     2-thiophenecarboxamidinomethyl                           3-thienyl      0     benzamidinomethyl                                        2-furyl        0     3,5-dichlorobenzamidinomethyl                            3-chloro-4-hydroxy-                                                                          0     4-pyridinecarboxamidinomethyl                            phenyl                                                                        p-methoxyphenyl                                                                              0     benzamidinomethyl                                        m-tolyl        0     3-pyridinecarboxamidinomethyl                            phenyl         0     propanecarboxamidinomethyl                               phenyl         0     butanecarboxamidinomethyl                                p-hydroxyphenyl                                                                              0     hexanecarboxamidinomethyl                                m-butoxyphenyl 0     benzamidinomethyl                                        methyl         1     acetamidinomethyl                                        methyl         1     benzamidinomethyl                                        isopropyl      1     4-pyridinecarboxamidinomethyl                            phenyl         1     butanecarboxamidinomethyl                                phenyl         1     3,5-dichlorobenzamidinomethyl                            phenyl         1     2-thiophenecarboxamidinomethyl                           p-hydroxyphenyl                                                                              1     benzamidinomethyl                                        p-chlorophenyl 1     4-pyridinecarboxamidinomethyl                            ______________________________________                                    

EXAMPLE CXXIV6-(D-2-[2-(4-Pyridinecarboxamidino)acetamido]-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

The title compound is prepared in 80% yield from6-(D-2-[2-aminoacetamido]-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and ethyl 4-pyridinecarboximidate, using the procedure of ExampleCXIX. The product has m.p. 195° C. (dec.). IR (KBr disc): 1775 cm⁻¹. NMR(DMSO-d₆): 9.3-8.8 ppm (m, 4H), 8.8-7.0 ppm (m, 4H), 7.75 ppm (d, 2H),7.25 ppm (d, 2H), 6.75 ppm (d, 2H), 5.85-5.45 ppm (m, 3H), 5.05 ppm (s,1H), 4.35 ppm (s, 2H), 1.5 ppm (s, 3H), 0.95 ppm (s, 3H).

EXAMPLE CXXV6-(D-2-[2-(3-Ethylureido)acetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

A mixture of 1.29 g. of6-(D-2-[2-aminoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,0.23 g. of ethyl isocyanate and 15 ml. of N,N-dimethylformamide isstirred at room temperature for 45 minutes. The filtered reactionmixture is then added dropwise with stirring to 300 ml. of ether, andthe precipitate which forms is filtered off. The solid is partitionedbetween water and ethyl acetate, and the pH is adjusted to 8.0. Theethyl acetate is removed and discarded. The pH of the aqueous phase isadjusted to 2.0, and the product is extracted into ethyl acetate. Thewashed (water) and dried (Na₂ SO₄) ethyl acetate is concentrated tosmall volume and the product crystallizes out. It is filtered off. Theyield of the title compound is 0.74 g. (49%), m.p. 162° C. (dec.). IR(KBr disc): 1785 cm⁻¹ (β-lactam). NMR (DMSO-d₆ /CDCl₃): 9.3-9.1 ppm(s,1H), 8.3 ppm (d,1H), 7.65-7.2 ppm (m,5H), 6.3-5.5 ppm (m,5H), 5.2 ppm(s,1H), 3.8 ppm (d,2H), 3.3-2.9 ppm (m,2H), 1.65 ppm (s,3H), 1.2-0.9 ppm(m,6H).

EXAMPLE CXXVI

Reaction of6-(D-2-[2-aminoacetamido]-2-phenylacetamido)-2,2-dimethyl-3(5-tetrazolyl)penamwith the appropriate isocyanate, according to the procedure of ExampleCXXV, provides the following compounds.

    ______________________________________                                         ##STR51##                                                                                   Melting  Infrared                                                     Yield   Point*   Spectrum                                                                             NMR Spectrum                                   Z      (%)     (°C.)                                                                           (cm.sup.-1)                                                                          (DMSO-d.sub.6 ; ppm)                           ______________________________________                                        anilino                                                                              38      158      1780   9.3-9.0(m,1H), 8.7-                                                           8.4(m,1H, 7.7-6.9(m.                                                          10H), 6.6-6.3(m,1h),                                                          5.9-5.45(m,3H), 5.2                                                           (s,1H), 3.95(d,2H),                                                           1.65(s,3H), 1.05(s,3H).                        methyl-                                                                              33      154      1785   9.25-9.05(m,1H), 8.15                          amino                          (d,1H), 7.6-7.15(m,5H),                                                       6.3-5.2(m,5H), 5.15(s,                                                        1H), 3.8(d,2H), 2.65                                                          (d,3H), 1.6(s,3H),                                                            1.05(s,3H).                                    ______________________________________                                         *with decomposition?                                                     

EXAMPLE CXXVII6-(D-2-[2-Phenoxyacetamido]-2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazol-5-yl)penam

To a stirred mixture of 1.0 g. of6-(D-2-amino-2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazol-5-yl)penam,and 0.91 ml. of triethylamine, in 20 ml. of methylene chloride, is added3 ml. of N,N-dimethylformamide. This solution is then cooled to 0° C.,and a solution of 0.375 g. of phenoxyacetyl chloride in 10 ml. ofmethylene chloride is added dropwise. The mixture is stirred for 30minutes after the end of the addition, and then the solvent is removedby evaporation in vacuo. The residue is dissolved in water. The aqueoussolution is extracted with ethyl acetate and then acidified to pH 2.4.The aqueous phase is again extracted with ethyl acetate, and the latterextract is dried using anhydrous sodium sulfate. Removal of the solventby evaporation in vacuo leaves 0.91 g. of crude product. The crudeproduct is purified by chromatography using Sephadex LH-20 as adsorbant,and eluting with water. The yield of purified product is 0.33 g. (30%),mp 180°-192° C. (dec.). IR (KBr disc): 1786, 1667, 1613 and 1515 cm⁻¹.NMR (CDCl₃ /DMSO-d₆): 9.13 ppm (d, J=7Hz, 1H), 8.58 ppm (d, J=8Hz, 1H),7.00-7.60 ppm (m, 9H), 5.90 ppm (d, J=8Hz, 1H), 5.60 ppm (m, 2H), 5.03ppm (s, 1H), 4.65 ppm (s, 2H), 1.57 ppm (s, 3H) and 0.97 ppm (s, 3H).

EXAMPLE CXXVIII6-(D-2-Phthalimido-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 1.07 g. of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and1.03 ml. of triethylamine, in 20 ml. of methylene chloride, is added, at0° C., a solution of phthalic anhydride in 10 ml. of methylene chloride.The mixture is stirred at ambient temperature for 1.5 hours, and thenthe solvent is removed by evaporation in vacuo. The residue is dissolvedin water at pH 7.8, and the water is washed with ethyl acetate. The pHof the aqueous phase is then lowered to 2.0 and the product is extractedinto ethyl acetate. The latter ethyl acetate is washed with water, driedusing anhydrous sodium sulfate, and evaporated in vacuo. This affords1.2 g. (92% yield) of the title compound, mp 185°-197° C. (dec.). IR(KBr disc): 1795, 1724 and 1639 cm⁻¹. NMR (CDCl₃ /DMSO-d₆): 8.67 ppm (m,3H), 8.25 ppm (d, J=8Hz, 1H), 7.50 ppm (m, 9H), 5.98 ppm (d, J=8Hz, 1H),5.65 ppm (m, 2H), 5.28 ppm (s, 1H), 1.67 ppm (s, 3H) and 1.10 ppm (s,3H).

EXAMPLE CXXIX6-(D-2-[3-Phenylthiouredio]-2-phenylacetamide)-2,2-dimethyl-3-(5-tetrazol)penam

To a stirred solution of 910 mg. of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, and0.61 ml. of triethylamine, in 20 ml. of methylene chloride, is added0.27 ml. of phenyl isothiocyanate. Stirring is continued for 2 hours atambient temperature, and then the solvent is removed by evaporation invacuo. The residue is dissolved in water at pH 7.8, and the water iswashed with ethyl acetate. The pH of the aqueous phase is then loweredto 2.0 and the product is extracted into ethyl acetate. The latter ethylacetate is washed with water, dried using anhydrous sodium sulfate, andevaporated in vacuo. This affords 707 mg. (64% yield) of the titlecompound mp 150°-167° C. (dec.). IR (KBr disc: 1786, 1681 and 1515 cm⁻¹.NMR (CDCl₃ /DMSO-d₆): 9.17 ppm (s, 1H), 8.27 ppm (m, 1H), 7.97 ppm (d,J=7Hz, 1H), 7.4 ppm (m, 10H), 6.3 ppm (d, J=7Hz, 1H), 5.63 ppm (m, 2H),5.27 ppm (s, 1H), 1.6 ppm (s, 3H) and 1.1 ppm (s, 3H).

EXAMPLE CXXX6-(D-2-[3-Guanylureido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 0.5 g of guanylsemicarbazide dihydrochloride(U.S. Pat. No. 3,579,514) in 5 ml. of water, is added dropwise, 0.184 g.of sodium nitrite in 2 ml. of water, at ca. 0° C. The resulting solutionis stirred for 10 minutes at ca. 0° C. A second solution is thenprepared from 1.14 g. of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, 20ml. of water, 6 ml. of dioxane and sufficient triethylamine to bring thepH to 8.0. The pH of the second solution is then lowered to 7.5, and thefirst solution is added dropwise at ca. 0° C. The resulting reactionmixture is stirred for 45 minutes. To it is then added a solutionprepared from 0.95 g. of sodium nitrite, 0.25 g. of guanylsemicarbazidedihydrochloride and 3 ml. of water. Stirring is continued for a further45 minutes, and then the reaction mixture is lyophilized. The residue isextracted with chloroform. The insoluble material is then suspended in20 ml. of water, the pH of which is then adjusted to 5.0. The solid isfiltered off and dried, to give 0.87 g. (71% yield) of the titlecompound, m.p. 192°-194° C. (dec.). IR (KBr disc: 1785 cm⁻¹ (β-lactam).NMR (in DMSO-d₆): 7.55 ppm (m, 5H), 5.85-5.55 ppm (m,3H), 5.10 ppm(s,1H), 1.55 ppm (s,3H), 0.95 ppm (s,3H).

In like manner, starting from6-(D-2-amino-2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,there is prepared a 94% yield of6-(D-2-[3-guanylureido]-2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,m.p. 186°-199° C. IR(KBr disc): 1783, 1695 and 1667 cm⁻¹. NMR (DMSO-d₆/D₂ O): 0.95 (s,3H), 1.55 (s,3H), 5.1 (s,1H), 5.4-5.8 (m,3H), 6.8(d,2H), 7.35 (d,2H).

EXAMPLE CXXXI

Following the procedure of Example CXXX and reacting the appropriate6-(2-amino-2-substituted-acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamwith diazotized guanylsemicarbazide, the following compounds areprepared.

    ______________________________________                                         ##STR52##                                                                            R.sup.7                                                               ______________________________________                                                methyl                                                                        isopropyl                                                                     cyclopentyl                                                                   3-cyclohexenyl                                                                1,4-cyclohexadienyl                                                           m-hydroxyphenyl                                                               p-chlorophenyl                                                                o-fluorophenyl                                                                3,4-dichlorophenyl                                                            p-methoxyphenyl                                                               p-tolyl                                                                       3,4-dimethoxyphenyl                                                           2-thienyl                                                                     3-thienyl                                                                     2-furyl                                                                       3-pyridyl                                                                     3-chloro-4-hydroxyphenyl                                              ______________________________________                                    

EXAMPLE CXXXII6-(D-2-Ureido-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

A mixture of 0.5 g. of2-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and94 mg. of potassium cyanate in 10 ml. of water is heated rapidly to 80°C., and then cooled rapidly to 25° C. The reaction mixture is stirred atambient temperature for 18 hours, and then filtered. The filtrate isacidified to pH 2.0, and the solid which precipitates is filtered off.It is dissolved in a small volume of ethanol, to which 0.067 ml. oftriethylamine is added, and then this solution is poured into 100 ml. ofether. The solid which precipitates is filtered off, giving 0.23 g. (38%yield) of the title compound as its triethylamine salt, m.p. 138°-150°C. (dec.). IR (KBr disc): 1785 cm⁻¹ (β-lactam) and 1670 cm⁻¹ (amide I).NMR (in DMSO-d₆ /D₂ O): 7.45 ppm (m,5H), 5.80-5.40 ppm (m,3H), 5.10 ppm(s,1H), 3.10 ppm (q,6H), 1.60 ppm (s,3H), 1.20 ppm (t,9H), 0.95 ppm(s,3H).

EXAMPLE CXXXIII6-(D-2-Sulfamoyl-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

A suspension of 1.5 g. of 2-sulfamoyl-2-phenylacetic acid in 15 ml. ofthionyl chloride is heated under reflux for 30 minutes, and then thethionyl chloride is removed by evaporation in vacuo. To the residue isadded 50 ml. of benzene and the mixture is evaporated to dryness invacuo again. The residue is then dissolved in 30 ml. of acetone, andadded dropwise, with stirring, at 0° C., to a solution of 0.84 g. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml. of water and 3.5ml. of 1N sodium hydroxide. During the addition, and for 30 minutesafterwards, the pH is maintained at 6.0-6.2. At this point, the reactionmixture is adjusted to pH 2.0, and the product is extracted into ethylacetate. The ethyl acetate is dried using anhydrous sodium sulfate, andthen it is evaporated to dryness in vacuo. The residue is dissolved inmethylene chloride containing 4.9 ml. of triethylamine. The solvent isagain evaporated to dryness in vacuo, giving 1.1 g. (58% yield) of thetitle compound as its triethylamine salt, m.p. 129°-139° C. (dec.). IR(KBr disc): 1770 cm⁻¹ (β-lactam). NMR (DMSO-d₆ /D₂ O): 7.60 ppm (m,5H),5.90-5.40 ppm (m,3H), 5.05 ppm (s,1H), 1.55 ppm (s,3H), 0.95 ppm (s,3H).

Preparation of 2-sulfamoyl-2-phenylacetic acid is described in BritishPat. No. 1,067,965.

EXAMPLE CXXXIV6-(D-2-[2-Guanylacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 405 mg. of p-nitrophenol in 10 ml. ofN,N-dimethylformamide is added 620 mg. of dicyclohexylcarbodiimidefollowed by 410 mg. of 2-guanylacetic acid hydrochloride. Stirring iscontinued for 4 hours, and then to this solution is added a solution of948 mg. of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamtriethylamine salt in 10 ml. of N,N-dimethylformamide. Stirring iscontinued overnight, and then the filtered reaction mixture is pouredinto 300 ml. of ether. A gummy precipitate forms, and the excess solventis removed by decantation. The gummy material is then slurried in 300ml. of methylene chloride containing 1 ml. of triethylamine. Thisaffords, after filtration, 0.4 g. (44% yield) of the title compound,m.p. 172°-176° C. (dec.). IR (KBr disc): 1780 cm⁻¹ (β-lactam). NMR (inDMSO-d₆ /D₂ O): 7.45 ppm (m,5H), 5.85 ppm (d,1H), 5.55 ppm (m,2 H), 5.05ppm (s,1H), 2.70 ppm (m,4H), 1.55 ppm (s,3H), 0.95 ppm (s,3H).

The 2-guanylacetic acid hydrochloride used in this Example is preparedfrom ethyl 2-cyanoacetate in a manner analogous to that described forthe preparation of 3-guanylpropionic acid hydrochloride.

EXAMPLE CXXXV6(D-2-[p-Guanidinobenzamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

A mixture of 2.15 g. of p-guanidinobenzoic acid hydrochloride and 75 ml.of thionyl chloride is heated under reflux for 18 hours. It is thencooled to 25° C., and concentrated to dryness in vacuo. The residue iswashed thoroughly with ethylene dichloride. This affords 1.7 g. ofp-guanidinobenzoyl chloride hydrochloride.

To a stirred solution of 0.854 g. of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamtrihydrate and 0.54 ml. of triethylamine in 10 ml. ofN,N-dimethylformamide is added, at 0° C., 0.468 g. of p-guanidinobenzoylchloride hydrochloride. Stirring is continued for 30 minutes, and then afurther 0.14 ml. of triethylamine and 0.124 g. of p-guanidinobenzoylchloride hydrochloride is added. After being stirred for a further 30minutes, the reaction mixture is filtered and the filtrate is addeddropwise to 300 ml. of ether. The solid which precipitates is filteredoff, and washed thoroughly with methylene chloride containingtriethylamine. This affords 0.8 g. (75% yield) of the title compound,m.p. 196°-200° C. IR (KBr disc): 1770 cm⁻¹ (β-lactam). NMR (in DMSO-d₆/D₂ O): 8.25-7.20 ppm (m,9H), 6.00 ppm (d,1H), 5.50 ppm (m,2H), 5.05 ppm(s,1H), 1.50 ppm (s,3H), 0.95 ppm (s,3H).

The preparation of p-guanidinobenzoic acid is described in Rec. Trav.Chim. Pay-Bas, 72, 643 (1952).

EXAMPLE CXXXVI

Reaction of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam or6-(D-2-amino-2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamwith the appropriate acid chloride hydrochloride, according to theprocedure of Example CXXXV, provides the following congeners. Acidchloride hydrochlorides are prepared from the corresponding acids by themethod of Hardcastle et al., Journal of Organic Chemistry, 31, 897(1966).

    __________________________________________________________________________     ##STR53##                                                                                         Melting                                                                             Infrared                                                           Yield                                                                              Point*                                                                              Spectrum                                           R.sup.1         (%)  (°C.)                                                                        (cm.sup.-1)                                                                        NMR Spectrum (ppm; DMSO-d.sub.6 /D.sub.2                                      O)                                            __________________________________________________________________________    D-2-(2-guanidinoacetamido)-                                                                   77   166-176                                                                             1780 7.80-7.25(m.5H), 5.85(d,1H), 5.55(m,2H),                                      5.10 (s,1H), 4.00(m,                          2-phenylacetyl                  2H), 1.50(s,3H), 0.95 (s,3H),                 D-2-(2-[Δ.sup.1 -imidazolin-2-                                                          37   170-177                                                                             1785 7.40(m,5H), 5.85(d,1H), 5.55(m,2H),                                           5.05(s,1H), 4.05(m,2H),                       ylamino]acetamido)-2-phenyl-    3.65(m,4H), 1.50(s,3H), 0.95(s,3H),           acetyl                                                                        D-2-(2-[4-guanidinophenyl]-                                                                   53   196-200                                                                             1780 7.80-7.05(m,9H), 5.80(d,1H), 5.45(m,2H),                                      5.05(s,1H), 3.6(s,                            acetamido)-2-phenylacetyl       2H), 1.50(s,3H), 0.90(s,3H),                  D-2-(3-guanylpropionamido)-                                                                   25   180-186                                                                             1785 7.45(m,5H), 5.85(d,1H), 5.55(m,2H),                                           5.05(s,1H), 2.70(m,4H),                       2-phenylacetyl                  1.55(s,3H), 0.95(s,3H),                       D-2-(2-[(N-methylguanyl)-                                                                     79   200-208                                                                             1772 9.70-9.05(m,2H), 8.00-7.10(m,10H),                                            5.95(d,1H), 5.60-5.30                         amino]acetamido)-2-phenyl-      (m,2H), 5.00(s,1H), 4.00(s,2H),                                               2.75(s,3H), 1,50(s,3H), 0.90                  acetyl                          (s,3H),                                       D-2-(2-[3-(guanyl)ureido]-                                                                    54   166-176                                                                             1785 7.45(m,5H), 5.80(d,1H), 5,50(m,2H),                                           5.05(s,1H), 3,85(m,2H),.                      acetamido)-2-phenylacetyl       1.55(s,3H), 0.95(s,3H),                       D-2-(2-[3-(N-methylguanyl)-                                                                   85   168-171                                                                             1786 0.95(s,3H), 1.55(s,3H), 2.9(s,3H),                                            3.85(m,2H), 5.1(s,1H),                        ureido[acetamido)-2-phenyl-                                                                              1667 5.4-5.95(m,3H), 7.5 (m,5H),                   acetyl                                                                        D-2-(2-[3-(N-ethylguanyl)-                                                                    60   165-175                                                                             1783 0.95(s,3H), 1.2(m,3H), 1,55(s,3H),                                            3.3(m,2H), 3,95(m,2H),                        ureido]acetamido)-2-phenyl-                                                                              1667 5.15 (s,1H), 5.5-5,85 (m,3H), 7.5(m,5H),      acetyl                                                                        D-2-(2-[3-(N-benzylguanyl)-                                                                   58   165-169                                                                             1786,                                                                              0.95(s,3H), 1.55(s,3H), 3.85(m,2H),                                           4.5(m,2H), 5.1(s,1H),                         ureido]acetamido)-2-phenyl-                                                                              1681 5.4-5.8(m,3H), 7.4(m,10H),                    acetyl                     1626                                               D-2-(2-[3-(N-p-chlorobenzyl-                                                                  59   178-190                                                                             1786,                                                                              0.95(s,3H), 1.55(s,3H), 3.9(m,2H),                                            4.5(m,2H), 5.15 (s,1H),                       guanyl)ureido]acetamido)-2-                                                                              1681,                                                                              5.4-5.85 (m,3H), 7.5(m,9H),                   phenylacetyl               1626                                               D-2-(2-[3-(N-[cyclohexylme-                                                                   68   178-185                                                                             1786,                                                                              0.95(s,3H), 1.55(m,14H), 3.1(m,2H),                                           3.9(m,2H), 5.15(s,1H),                        methyl]guanyl)ureido]acet- 1681 5.4-5.8(m,3H), 7.45(m,7H), 8.6(m,2H)          amido)-2-phenylacetyl                                                         D-2-(2-[3-(guanyl)ureido]-                                                                    62   182-188                                                                             1786,                                                                              0.95 (s,3H), 1.55 (s,3H), 3.8 (m,2H),                                         5.05 (s,1H), 5.4-5.8                          acetamido)-2-(4-hydroxy-   1695,                                                                              (m,3H), 6.8 (d,2H), 7.3 (d,2H).               phenyl)acetyl              1667                                               __________________________________________________________________________     *with decomposition                                                      

The acid chloride hydrochlorides used in this Example are prepared fromthe corresponding acids, using thionyl chloride. 2-(Guanylureido)aceticacid is prepared by the method of Frankel and Sheradsky, J. Chem. Soc.(London), C, 2698 (1967); 2-(p-guanidinophenyl)acetic acid is preparedby the method of Leanza et al., Nature, 207, 1395 (1965); and3-guanylpropionic acid is prepared by the method of McElvain andSchroeder, J. Amer. Chem. Soc., 71, 40 (1949).

EXAMPLE CXXXVII

Following the procedure of Example CXXXV and reacting the appropriate6-(2-amino-2-substituted-acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamwith 2-guanidinoacetyl chloride hydrochloride, the following compoundsare prepared:

    ______________________________________                                         ##STR54##                                                                               R.sup.7                                                            ______________________________________                                                methyl                                                                        isopropyl                                                                     allyl                                                                         cyclohexyl                                                                    3-cyclohexenyl                                                                1,4-cyclohexadienyl                                                           p-hydroxyphenyl                                                               p-chlorophenyl                                                                m-methoxyphenyl                                                               o-fluorophenyl                                                                3,4-dichlorophenyl                                                            p-tolyl                                                                       3-chloro-4-hydroxyphenyl                                                      2-thienyl                                                                     3-thienyl                                                                     2-furyl                                                                       3-pyridyl                                                                     5-tetrazolyl                                                                  5-ethyl-2-thienyl                                                     ______________________________________                                    

EXAMPLE CXXXVIII6-(D-2-[3-(2-Furoyl)ureido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred suspension of 5.0 g. of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 50ml. of methylene chloride is added 2.72 g. of triethylamine. After 10minutes, the solution is dried (Na₂ SO₄), and then it is concentrated todryness in vacuo giving the triethylamine salt of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam.

To 948 mg. of the above triethylamine salt, in 10 ml. of methylenechloride, at 0° C., is added 274 mg. of 2-furoyl isocyanate dissolved ina small volume of methylene chloride. After 10 minutes, the solvent isremoved in vacuo. The residue partitioned between ethyl acetate andwater, and the pH is adjusted to 7.7. The ethyl acetate is removed anddiscarded. The pH of the remaining aqueous phase is adjusted to 2.5 andthe product is extracted into ethyl acetate. The ethyl acetate is washedwith water, followed by brine, and then it is evaporated to dryness invacuo. The residue is dissolved in methylene chloride containing 145 mg.of triethylamine and again the solution is evaporated to dryness invacuo. This affords 930 mg. (76% yield) of the title compound or itstriethylamine salt, mp. 90°-115° C. (dec.). IR (KBr disc): 1778 cm⁻¹(β-lactam). NMR (in CDCl₃): 8.2-7.2 (m), 6.5 (m), 6.0-5.4 (m), 1.7 (s),1.1 (s).

EXAMPLE CXXXIX

Using the procedure of Example CXXXVIII, and reacting either6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam or6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam withthe appropriate-acyl isocyanate, acyl isothiocyanate or sulfonylisocyanate, the following compounds are prepared

    __________________________________________________________________________     ##STR55##                                                                                        Infrared                                                                  Yield                                                                             Spectrum                                                  R.sup.1         (%) (cm.sup.-1)                                                                         NMR Spectrum (CDCl.sub.3 ; ppm)                     __________________________________________________________________________    *2-(3-acetylureido)-2-phenyl-                                                                 98  1785, 1680,                                                                         7.4(s), 6.0-5.4(m), 5.3(s), 2.1(m), 1.6(s),                                   1.1(s),                                             acetyl              1495                                                      *2-(3-butyrylureido)-2-phenyl-                                                                    1770, 1695                                                                          7.2(s,5H), 5.8(m,3H), 5.2(s,1H), 2.2(m,2H),                                   1.4(s,                                              acetyl                    3H), 0.9(s,3H).                                     *2-(3-[chloroacetyl]ureido)-2-                                                                84  1770, 1695,                                                                         7.8-7.3(m,5H), 6.0-5.5(m,4H), 5.3(s,1H),                                      4.3(s,2H),                                          phenylacetyl        1530  1.5(s,3H), 1.1(s,3H).                               *2-(3-[3-pyridylcarbonyl]-                                                                    88  1785, 1695,                                                                         9.0-8.0(m,3H), 7.7-7.3(s,6H), 6.0-5.3(n,3H),                                  1.6(s,3H),                                          ureido)-2-phenylacetyl                                                                            1495  1.2(s,3H).                                          *2-(3-benzoylureido)-2-phenyl-                                                                48  1785, 1670,                                                                         8.6-7.3(m,10H), 6.3-5.7(m.2H), 5.4(s,2H),                                     1.6(s,3H),                                          acetyl              1540, 1515,                                                                         1.1(s,3H).                                                              1480                                                      *2-(3-[3,5-dibromobenzoyl]-                                                                   49  1770, 1670,                                                                         8.3-7.3(m,8H), 6.1-5.4(m,3H), 5.3(s,1H),                                      1.6(s,3H),                                          ureido)-2-Phenylacetyl                                                                            1560, 1490                                                                          1.1(s,3H).                                          *2-(3-[4-pyridylcarbonyl]-                                                                    68  1785, 1670,                                                                         9.0-7.3(m,9H), 6.0-5.3(m,4H), 1.5(s,3H),                                      1.0(s,3H).                                          ureido)-2-phenylacetyl                                                                            1505                                                      *2-(3-propionylureido)-2-                                                                     80  1770, 1695,                                                                         7.7-7.3(m,5H), 6.5(m,2H), 6.0-5.3(m,5H),                                      1.5(s,3H),                                          phenylacetyl    8-1540                                                                            1.3-1.0(m,6H).                                            *2-(3-[cyclopropylcarbonyl]-                                                                  83  1770, 1695                                                                          7.4(s,5H), 5.8∝5.2(s,4H), 1.4(s,4H),                                   0.9(s,7H).                                          ureido)-2-phenylacetyl                                                        *2-(3-[1-adamantylcarbonyl]-                                                                  76  1785, 1680                                                                          7.2(s,5H), 5.8-5.2(s,4H), 1.4(s,3H),                                          0.9(s,3H).                                          ureido)-2-phenylacetyl                                                        *2-(3-benzoylthioureido)-2-                                                                   79  1770, 1680,                                                                         7.7-7.2(s), 6.0-5.3(m), 2.05(s), 1.6(s),                                      1.1(s).                                             phenylacetyl        1480                                                      *2-(3-[2-furoyl]thioureido)-                                                                  73  1770, 1680,                                                                         7.7-7.0(m), 6.6(m), 6.0-5.4(m), 5.3(s), 2.1(s),                               1.6                                                 2-phenylacetyl      1590, 1515                                                                          (s), 1.1(s).                                        2-(3-[p-toluenesulfonyl]-                                                                     70  1800, 1600                                                                          7.9(d,2H), 7.4(m,8H), 5.5(m,3H), 5.2(s,1H),                                   2.4(s,3H),                                          ureido)-2-phenylacetyl    1.6(s,3H), 1.05(s,3H).                              3-acetylureido  58  1790, 1695                                                                          10.45(s,1H), 9.35(d,1H), 5.8(m,2H), 5.35(s,1H),                               2.1(s,3H),                                                                    1.7(s,3H), 1.15(s,3H),                              3-(2-furoyl)ureido                                                                            60  1795, 1695                                                                          9.33(m,2H), 7.5(m,3H), 6.6(m,2H), 5.8(m,2H),                                  5.45(s,1H),                                                                   1.8(s,3H), 1.2(s,3H),                               3-(p-toluenesulfonyl)-                                                                        91  1795, 1695                                                                          7.7(q,4H), 7.1(d,1H), 5.8-5.4(m,2H), 5.3(s,1H),                               2.4(s,3H),                                          ureido                    1.7(s,3H), 1.07(s,3H).                              **2-(3-[2-phenylacetyl]-                                                                      82  1770, 1685                                                                          7.7-6.9(m,10H), 5.8-5.2(m,4H), 2.0(m,2H),                                     1.6-0.2(m,10H).                                     ureido)-2-phenylacetyl                                                        **2'-(3-[benzyloxycarbonyl]-                                                                  50  1770, 1730                                                                          7.8-6.8(m,10H), 5.9-5.2(m,4H), 2.0(s,1H),                                     1.9-1.0(m,15H).                                     ureido)-2-phenylacetyl                                                                            1680                                                      **2-(3-[acetyl]thioureido)-                                                                   79  1760, 1660                                                                          7.7-7.1(m,5H), 5.8-5.3(m,4H), 2.1(m,4H),                                      1.5(s,3H), 1.0(s,3H),                               2-phenylacetyl                                                                **2-(3-[3-methyl-5-isoxa-                                                                     64  1770, 1695                                                                          7.8-7.2(m,6H), 7.0(s,1H), 5.7 (m,4H),                                         5.3(s,1H), 2.4(s,3H)                                zolylcarbonyl]ureido)-2-  2.2(s,1H), 1.5(s,3H), 1.0(s,3H),                    phenylacetyl                                                                  __________________________________________________________________________     *This compound is isolated as its triethylamine salt.                         **This compound is isolated as its sodium salt                           

EXAMPLE CXL

Using the procedure of Example CXXXVIII, and reacting6-(2-amino-2-substituted-acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamor6-(2-[2-aminoacetamido]-2-substituted-acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamwith the appropriate acyl isocyanate, provides the following compounds

    ______________________________________                                         ##STR56##                                                                    R.sup.7             Z             m                                           ______________________________________                                        methyl          2-furancarboxamido                                                                              0                                           methyl          benzamido         0                                           isopropyl       acetamido         0                                           isopropyl       2-furancarboxamido                                                                              1                                           phenyl          p-chlorobenzamido 0                                           phenyl          m-bromobenzamido  0                                           phenyl          0-fluorobenzamido 0                                           phenyl          3,4-dichlorobenzamido                                                                           0                                           phenyl          p-methoxybenzamido                                                                              0                                           phenyl          m-n-butoxybenzamido                                                                             0                                           phenyl          3,4-dimethoxybenzamido                                                                          0                                           phenyl          p-isopropylbenzamido                                                                            0                                           p-hydroxyphenyl 2-furancarboxamido                                                                              0                                           p-hydroxyphenyl benzamido         0                                           p-chlorophenyl  propionamido      0                                           m-methoxyphenyl 3,4-dichlorobenzamido                                                                           0                                           p-tolyl         2-thiophenecarboxamido                                                                          0                                           3,5-dichlorophenyl                                                                            3-thiophenecarboxamido                                                                          0                                           3-chloro-4-hydroxyphenyl                                                                      2-furancarboxamido                                                                              0                                           3-chloro-4-hydroxyphenyl                                                                      benzamido         0                                           2-thienyl       2-furancarboxamido                                                                              0                                           2-thienyl       benzamido         0                                           3-thienyl       p-chlorobenzamido 0                                           3-thienyl       n-butyramido      0                                           2-furyl         3-furancarboxamido                                                                              0                                           3-furyl         p-iodobenzamido   0                                           3-pyridyl       benzamido         0                                           1,4-cyclohexadienyl                                                                           2-furancarboxamido                                                                              0                                           methyl          benzamido         1                                           phenyl          2-furancarboxamido                                                                              1                                           p-hydroxyphenyl 3,5-dichlorobenzamido                                                                           1                                           3-chloro-4-hydroxyphenyl                                                                      benzamido         1                                           2-thienyl       2-furancarboxamido                                                                              1                                           3-thienyl       benzamido         1                                           3-chloro-4-hydroxyphenyl                                                                      acetamido         0                                           p-chlorophenyl  propionamido      0                                           2-thienyl       n-butyramido      0                                           3-furyl                                                                       isopropyl       n-hexanoyl        0                                           phenyl          isobutyramido     0                                           phenyl          acetamido         1                                           p-hydroxyphenyl propionamido      1                                           ______________________________________                                    

EXAMPLE CXLI6-(D-2-[4-Aminobenzamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

A solution is prepared by suspending 1.05 g. of6-(D-2-[4-nitrobenzamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamin 50 ml. of water, and adjusting the pH to 7.3 using sodium bicarbonatesolution. To this solution is then added 1.0 g. of 10% palladium oncarbon, and the mixture is shaken under an atmosphere of hydrogen, at apressure of ca. 40 psi, until hydrogen uptake ceases. The spent catalystis removed by filtration, and the aqueous solution is lyophilized. Thisaffords 0.91 g. of crude product. A portion of the crude product ispurified further by column chromatography using Sephadex LH-20 andeluting with water. The purified product has mp 260°-272° C. IR(KBRdisc): 1770 and 1626 cm⁻¹. NMR (D₂ O): 7.6-7.0 ppm (m, 7H), 6.5 ppm (d,J=9 Hz, 2H), 5.6.5.4 ppm (m, 3H), 5.2 ppm (s, 1H), 1.4 ppm (s, 3H) and0.88 ppm (s, 3H).

EXAMPLE CXLII6-(D-2-[2-(4-Aminophenyl)acetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

The title compound is prepared in 23% yield by hydrogenation of6-(D-2-[2-(4-nitrophenyl)acetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,using the procedure of Example CXLI. The product has mp 260°-270° C.(dec.). IR(KBr disc): 1770, 1653 and 1515 cm⁻¹. NMR (O₂ O): 7.6-6.8 ppm(m), 5.6 ppm (m), 5.2 ppm (s), 3.4 ppm (s), 1.3 (s) and 0.8 (s).

EXAMPLE CXLIII6-(L-2-Hydroxy-2-phenylacetamido)-2,2-dimethyl-3-dimethyl-3-(5-tetrazolyl)penam

A mixture of 0.152 g of L-mandelic acid, 0.115 g of N-hydroxysuccinimideand 0.206 g of N,N-dicyclohexycarbodiimide in 10 ml of tetrahydrofuranin a 25 ml flask, is stirred at ambient temperature overnight. In aseparate flask, 0.216 g of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penamand 0.23 ml of triethylamine in 10 ml of chloroform and 10 ml ofmethylene chloride is stirred overnight. The mixture in the first flaskis then filtered, and the filtrate is added slowly to the second flask.The resultant mixture is stirred for 4 hours at ambient temperature. Thesolvents are then removed by evaporation in vacuo, and the residue ispartitioned between ethyl acetate and water. The pH is adjusted to 4.7(1 N sodium hydroxide), and then the organic phase is withdrawn anddiscarded. The pH of the aqueous phase is then reduced to 2.0 (5%hydrochloric acid), and the product is extracted with ethyl acetate. Thesolvent is washed with dilute hydrochloric acid followed by brine, driedusing anhydrous sodium sulfate, and then it is added dropwise withstirring to 400 ml of hexane. The precipitate which forms is filteredoff, giving 170 mg of6-(L-2-hydroxy-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam.NMR (in DMSO-d₆): 8.16 ppm (broad singlet, 1H, OH), 7.47-7.04 ppm(multiplet, 6H, aromatic protons and NH), 5.73-5.50 ppm (multiplet, 2H,C-5 and C-6 hydrogens), 5.31 and 5.07 ppm (2 singlet, 2H, C-3 hydrogenand side-chain methine hydrogen), 1.67 and 1.10 ppm (2 singlets, 6H, C-2methyl hydrogens).

EXAMPLE CXLIV6-(D-2-Hydroxy-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

The procedure of Example CXLIII is repeated, except that the L-mandelicacid used therein is replaced by an equivalent amount of D-mandelicacid. This affords a 77% yield of the title compound. NMR (in DMSO-d₆):8.40-8.20 ppm (broad doublet, 1H, NH), 7.48-7.18 ppm (multiplet, 6H,aromatic hydrogens and OH), 5.31 and 5.07 ppm (2 singlets, 2H, C-3hydrogen and side-chain methine hydrogen), 1.65 and 1.07 ppm (2singlets, 6H, C-2 methyl hydrogens).

EXAMPLE CXLV6-(2-Carboxy-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 150 mg of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 5 ml of water is addeddropwise dilute sodium hydroxide to give a pH of 6.1. To this solutionis then added 150 mg of phenylamalonic acid, followed by 120 mg of1-ethyl-3-(3-dimethylaminoprop-1-yl)carbodiimide. The solution isstirred for a further 3.5 hours, during which time the pH is maintainedin the range from 6.1 to 6.3 by the dropwise addition of dilutehydrochloric acid. At this point, the pH is raised to 7.3 by theaddition of saturated sodium bicarbonate solution, and the reactionmixture is extracted with ethyl acetate. The extract is discarded. Theaqueous phase is then acidified to pH 2 using dilute hydrochloric acid,and it is again extracted with ethyl acetate (two 30-ml portions). Thelatter extract is dried, and concentrated to a volume of about 25 ml. Tothis solution is then added a solution of 180 mg of sodium 2-ethylhexanoate in 1.25 ml of ethyl acetate. The precipitate which formsis filtered off to give 176 mg of the disodium salt of6-(2-carboxy-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. Theinfrared spectrum of the product (KBr disc) shows absorptions at 1765cm⁻¹ (β-lactam carbonyl), 1670 cm⁻¹ (amide I band) and 1600 cm⁻¹(carboxylate carbonyl). The NMR spectrum (in D₂ O) shows absorptions at7.40 ppm (broad singlet, aromatic hydrogens), 5.70 ppm (doublet, C-5hydrogen), 5.50 ppm (doublet, C-6 hydrogen), 5.25 ppm (2 singlets, C-3hydrogen), 1.50 ppm (2 singlets, C-2 methyl hydrogens) and 0.95 ppm (2singlets, C-2 methyl hydrogens).

EXAMPLE CXLVI

Following the procedure of Example CXLV, and replacing the phenylmalonicacid used therein by an equimolar amount of the appropriate2-substituted malonic acid, there is produced

6-(2-carboxy-2-[2-furyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-carboxyvaleramido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-carboxy-2-[p-chlorophenyl]acetamido-2,2-dimethyl-3-(5-tetrazolyl)penam

6-(2-carboxy-2-[p-tolyl]acetamido-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-carboxy-2-[1,4-cyclohexadienyl]acetamido-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-carboxy-2-cyclohexylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamand

6-(2-carboxy-b 3-phenylpropionamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

respectively.

EXAMPLE CXLVII6-(2-Carboxy-2-[2-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred suspension of 370 mg (0.002 mole) of 2-(2-thienyl)malonicacid (Netherlands Pat. No. 6805524) in 4 ml. of water is added 480 mg.(0.002 mole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, and then thepH is adjusted to 6.5 using 20% sodium hydroxide. The resulting clearsolution is cooled to 0° C. and 384 mg. (0.002 mole) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride is added.The solution is stirred for 3.5 hours at 0° C., with the pH maintainedbetween 6 and 7 using 1 N hydrochloric acid. At this point, the pH ofthe solution is then lowered to 2.0 and the mixture is extracted withethyl acetate. The extracts are combined, dried and then concentrated toca. 15 ml. To this solution is added a solution of 665 mg (0.040 mole)of sodium 2-ethylhexanoate in 2.6 ml., and then the solid whichprecipitates is filtered off, and dried, to give 462 mg. (51% yield) of6-(2-carboxy)-2-[2-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamas it disodium salt. The infrared spectrum of the product (KBr disc)shows absorption bands at 1780 cm⁻¹ (β-lactam), 1670 cm⁻¹ (amide I),1615 cm⁻¹ (carboxylate) and 1560 cm⁻¹ (amide II). The NMR spectrum (inD₂ O) shows absorptions at 7.50-7.1 ppm (multiplet, thienyl hydrogens),5.90 ppm (doublet of doublets, C-6 hydrogen), 5.65 ppm (doublet, C-5hydrogen), 5.40 ppm (doublet, C-3 hydrogen), 1.68 ppm (doublet, C-2methyl hydrogens) and 1.00 ppm (doublet, C-2 methyl hydrogens).

EXAMPLE CXLVIII6-(2-Carboxy-2-[3-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

Reaction of 500 mg. (2.69 mmole) of 2-(3-thienyl)malonic acid (BritishPat. No. 1,125,557) with 645 mg. (2.69 mmole) of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, according to the procedureof Example CXLVII, affords 810 mg. (67% yield) of6-(2-carboxy-2-[3-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamas its disodium salt. The infrared spectrum of the product KBr disc)shows absorptions at 1775 cm⁻¹ (β-lactam), 1670 cm⁻¹ (amide I), 1620cm⁻¹ (carboxylate) and 1525 cm⁻¹ (amide II). The NMR spectrum (D₂ O)shows absorptions at 7.80-7.00 ppm (multiplet, thienyl hydrogens), 5.88ppm (doublet, C-6 hydrogen), 5.65 ppm (doublet of doublets, C-5hydrogen), 5.40 ppm (doublet, C-3 hydrogen), 1.60 ppm (doublet, C-2methyl hydrogens) and 1.00 ppm (doublet, C-2 methyl hydrogens).

EXAMPLE CIL6-(2-Sulfo-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred of 240 mg. of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in5 ml. of methylene chloride is added 0.254 ml of triethyl amine. This isstirred for a further 45 minutes, and then it is cooled to about 0° C.To it is then added a solution, in 6 ml. of methylene chloride, of 389mg. of the mixed carbonic-carboxylic anhydride formed by reacting thebis-triethylamine salt of 2-sulfo-2-phenylacetic acid with oneequivalent of ethyl chloroformate (Nicolaus, et al., Annali di Chimica[Rome], 53, 14 [1963]). The reaction mixture is then stirred at about 0°C. for a further 1.5 hours after the addition of the anhydride solution.At this point, the reaction mixture is filtered and then a solution of288 mg of sodium 2-ethylhexanoate in ethyl acetate is added. Theprecipitate which forms is filtered off, giving the crude product as itsdisodium salt. The crude product is purified by dissolving it in waterand adding the solution to a column of 25 g of Sephadex LH-20 (PharmaciaFine Chemicals, Inc.) made up in water. The column is eluted with water,taking fractions, and the composition of the fractions is assayed bythin-layer chromatography. The fractions containing the pure product arecombined and lyophilized, giving 117 mg. of the disodium saalt of6-(2-sulfo-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl) penam. Theinfrared spectrum (KBr disc) of the product shows absorptions at 1765cm⁻¹ (β-lactam carbonyl) and 1660 cm⁻¹ (amide I band). The NMR spectrum(in D₂ O) shows absorptions at 7.60-7.20 ppm (multiplet, aromatichydrogens), 5.70 and 5.50 ppm (2 multiplets, C-5 and C-6 hydrogens),5.20 ppm (multiplet, methine hydrogen), 5.00 ppm (singlet, C-3hydrogen), 1.50 ppm (2 singlets, C-2 hydrogens) and 0.95 ppm (2singlets, C-2 methyl hydrogens).

EXAMPLE CL6-(2-[5-Indanyloxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

Reaction of 592 mg. (2.0 mmole) of 5-indanyl 2-phenylmalonate with 480mg. (2.0 mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, accordingto the procedure of Example CXLVII affords 680 mg. (63% yield) of6-(2-[5-indanyloxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamas its sodium salt. The infrared spectrum (KBr disc) of the productshows absorption bands at 1780 cm⁻¹ (β-lactam), 1705 cm⁻¹ (ester), 1680cm⁻¹ (amide I) and 1565 cm⁻¹ (amide II). The NMR spectrum (D₂ O) showsabsorption bands at 7.80-6.80 ppm (multiplet, aromatic hydrogens), 5.70ppm (multiplet, C-5 and C-6 hydrogens), 5.25 ppm (doublet, C-3hydrogen), 2.60-2.00 ppm (multiplet, C-1 and C-3 indanyl hydrogens),2.00-1.80 ppm (multiplet, C-2 indanyl hydrogens), 1.35 ppm (doublet, C-2methyl hydrogens) and 0.90 ppm (doublet, C-2 methyl hydrogens).

EXAMPLE CLI6-(2-Phenoxycarbonyl-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

A stirred solution of 1.80 g. of phenyl chlorocarbonyl ketene (U.S. Pat.No. 3,679,801) in 20 ml. of chloroform is cooled to -40° C., and then0.94 g of phenol is added. Stirring is con tinued at -40° C. for afurther 20 minutes, and then a solution of 2.40 g. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam and 1.40 ml of triethylaminein 50 ml. of chloroform is added dropwise. The cooling bath is removed,and the mixture is stirred for a further 30 minutes. The mixture isfiltered, and the chloroform is evaporated in vacuo to give crude6-(2-phenoxycarbonyl-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,as its triethylamine salt.

EXAMPLE CLII

The procedure of Example CLI is repeated except that the phenylchlorocarbonyl ketene used therein is replaced by an equimolar amount ofp-chlorophenyl chlorocarbonyl ketene, 2-furyl chlorocarbonyl ketene and3-thienyl chlorocarbonyl ketene, respectively. There is produced:

6-(2-phenoxycarbonyl-2-[p-chlorophenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-phenoxycarbonyl-2-[2-furyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,and

6-(2-phenoxycarbonyl-2-[3-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

respectively.

When the procedure of Example CLI is repeated, and the phenol usedtherein is replaced by an equimolar amount of the appropriatesubstituted phenol, the products are:

6-(2-[m-methoxyphenoxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[-methylphenoxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[5-indanyloxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[p-nitrophenoxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[m-bromophenoxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[o-fluorophenoxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

6-(2-[p-cyanophenoxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,and

6-(2-[3,4-dichlorophenoxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam.

EXAMPLE CLIII6-(2-carbamoyl-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 523 mg. (0.001 mole) of6-(2-[p-nitrophenoxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamand 101 mg of triethylamine in 50 ml. of chloroform is added 1 ml of a 1M solution of ammonia in methanol, at -30° C. Stirring is continued for4 hours without external cooling and then evaporation in vacuo leavesthe crude product as its triethylamine salt.

EXAMPLE CLIV6-(D-2-sulfoamino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred suspension of 2.13 g. (0.005) mole of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 50ml. of methylene chloride is added 0.84 ml. (0.006 mole) oftriethylamine. The mixture is stirred until most of the solid dissolves.To this solution is then added approximately 2 g. of pulverized Linde 4A molecular sieves, and stirring is continued for an additional onehour. The molecular sieves are removed by filtration, and the filtrateis cooled to 0° C. To this cooled solution is added, portionwise, over 5minutes, 0.84 g. (0.006 mole) of trimethylaminesulfur trioxide complex.The solution is stirred at 0° C. for 5 minutes, and then at ambienttemperature for 2.5 hours. A solution of 2.5 g. of sodium2-ethylhexanoate in 10 ml. of 1-butanol is then added. The resultingprecipitate is filtered, dissolved in 20 ml. of water and cooled to 0°C. The pH of the reaction is adjusted to 5.0 (glacial acetic acid) andthe resulting cloudy solution is stirred for 1 hour. After filtrationthrough diatomaceous earth, the filtrate is added dropwise with stirringto 700 ml. of cold (0° C.) acetone. The resulting precipitate iscollected, and dried, to yield 1.80 g. (65.3% yield) of6-(D-2-sulfoamino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamas its disodium salt. The infrared spectrum (KBr disc) shows absorptionsat 1770 cm⁻¹ (β-lactam), 1660 cm⁻¹ (amide I) and 1550 cm⁻¹ (amide II).The NMR spectrum (D₂ O) shows absorptions at 7.46 ppm (S, 5H aromatichydrogens), 5.64 ppm (q, 2H, C-5 and C-6 hydrogens), 5.33 ppm) S, 1H,methine hydrogen), 5.10 ppm (S, 1H, C-3 hydrogen), 1.58 ppm (S, 3H, C-2methyl hydrogens) and 1.00 ppm (S, 3H, C-2 methyl hydrogens). [α]_(D) ²⁵=108° (H₂ O).

Analysis--Calcd. for C₁₆ H₁₇ N₇ O₅ S₂ Na₂ (percent): C, 34.85; H, 4.20;N, 17.78; S, 11.63. Found: (Percent): C, 35.02; H, 4.31; N, 17.82; S,11.91.

EXAMPLE CLV

Reaction of the appropriate6-(2-amino-2-substituted-acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamwith the sulfur trioxide-trimethylamine complex, according to theprocedure of Example CLIV provides the following compounds:

    ______________________________________                                         ##STR57##                                                                            R.sup.7                                                               ______________________________________                                                methyl                                                                        isopropyl                                                                     cyclopentyl                                                                   3-cyclohexenyl                                                                1,4-cyclohexadienyl                                                           benzyl                                                                        p-chlorobenzyl                                                                p-hydroxyphenyl                                                               m-methoxyphenyl                                                               m-bromophenyl                                                                 o-fluorophenyl                                                                p-tolyl                                                                       3-chloro-4-hydroxyphenyl                                                      3,4-dichlorophenyl                                                            3,4-dimethoxyphenyl                                                           2-thienyl                                                                     3-thienyl                                                                     2-furyl                                                                       3-pyridyl                                                             ______________________________________                                    

EXAMPLE CLVI6-(D-2-[Carboxymethoxy]acetamido-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 2.59 g. (6.0 mmole) of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamtrihydrate and 1.70 ml. (12.2 mmole) of triethylamine in 70 ml. ofmethylene chloride, at 0°-5° C., is added a solution of 1.40 g. (12.0mmole) of diglycolic anhydride in 30 ml. of methylene chloride. Thesolution is stirred at 0°-5° C. for 1 hour and then it is extracted with200 ml. of 10% sodium bicarbonate solution. The pH of the aqueous phaseis adjusted to 2.0 and the product is extracted into ethyl acetate. Thesolvent is dried (MgSO₄), and then concentrated in vacuo, to give 820mg. (28% yield) of the title compound. IR (KBr disc): 1780 cm⁻¹(β-lactam) and 1650 cm⁻¹ (amide I). NMR (in DMSO-d₆): 7.41 ppm (m, 5H),5.55-5.90 ppm (m, 3H), 5.24 ppm (S, 1H), 4.17 ppm (S, 2H), 4.10 ppm (s,2H), 1.57 ppm (s, 3H), 0.99 (s, 3H).

EXAMPLE CLVII6-(D-2-[4-Carboxy-2,3-propionamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazol-5-yl)penam

The title compound is prepared in 73% yield from6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam andepoxysuccinic anhydride, using the method of Example CLVI. IR. (KBrdisc): 1790 cm⁻¹ (β-lactam) and 1665 cm⁻¹ (amide I). NMR (in DMSO-d₆):7.42 ppm (m, 5H), 5.55-5.85 ppm (m, 3H), 5.27 ppm (s, 1H), 3.87 ppm (s,2H), 1.60 ppm (s, 3H), 1.02 ppm (s, 3H).

EXAMPLE CLVIII6-(2-[2-(Carboxymethyl)phenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

An ice-bath cooled, stirred mixture of 1.94 g (10 mmol) ofo-phenylenediacetic acid, and 60 ml. of water is adjusted to pH 5.5 bythe careful addition of 6 N sodium hydroxide. The resulting solution istreated with 1.92 g (10 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and stirringis continued for 30 minutes, with the pH being maintained at 5.5 by theaddition of 6.0 N hydrochloric acid. A solution consisting of 2.4 g. (10mmol) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam and 30 ml. of water(adjusted to pH 7) is added to the first mentioned solution and stirringand cooling is continued for an hour. The aqueous solution is washedthree times with 30 ml. portions of ethyl acetate, and is then adjustedto pH 2.5 with 6 N hydrochloric acid. This solution is extracted twicewith 40 ml. portions of ethyl acetate, and the combined extracts arewashed with 50 ml. of water. After being dried over anhydrous sodiumsulfate, the extract is evaporated under reduced pressure to furnish acolorless foam: yield 3 g. The foam is dissolved in 50 ml. of ethylacetate and then it is treated with 2.4 g. (14.5 mmol) of sodium2-ethylhexanoate in 30 ml. of ethyl acetate. The title compoundprecipitates as the sodium salt: yield 3.4 g (74%) IR (KBr) 1770, 1667,and 1587 cm⁻¹ NMR (D₂ O): 7.25 ppm (s, 4H), 5.70 (d, 1H), 5.40 (d, 1H),5.25 (s, 1H), 3.70 (s, 2H), 3.60 (s, 2H), 1.50 (s, 3H), 1.00 (s, 3H).

EXAMPLE CLIX6-(2-Acetyl-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a solution of 700 mg (3.92 mmoles) of 1-carboxy-1-phenyl-2-propanonein 35 ml. of dry tetrahydrofuran is added 453 mg (3.92 mmoles) ofN-hydroxysuccinimide (dissolved in a small portion of drytetrahydrofuran), followed by 811 mg. (3.92 mmoles) ofdicyclohexylcarbodiimide dissolved in a small portion of drytetrahydrofuran. The reaction mixture is allowed to stir at roomtemperature for approximately three hours. The reaction mixture is thenfiltered and the yellow filtrate is added dropwise, with stirring, to acooled (0° C.) solution of 720 mg. (3 mmoles) of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam and 606 mg. of triethylaminein 15 ml. of methylene chloride. The resulting solution is stirred for45 minutes, and then the solvent is removed by evaporation in vacuo. Tothe residue is added 50 ml. of water and 50 ml. of ethyl acetate, andthe pH is adjusted to 7.8 using sodium bicarbonate solution. The ethylacetate layer is removed and discarded. To the aqueous phase is added afurther quantity of ethyl acetate and the pH is adjusted to 2.5.

The ethyl acetate is removed, washed with water, washed with sodiumchloride solution, and then dried using anhydrous sodium sulfate. To thedried solution is added 0.42 ml. (3 mmole) of triethylamine, and thenthe solvent is removed giving the title compound as its triethylaminesalt. The yield is 540 mg. (36%). IR (CHCl₃ solution): 1780 cm⁻¹. NMR(CDCl₃): 7.6-7.2 ppm (m, 5H), 6.0-5.6 (m, 4H), 5.4 ppm (s, 1H), 3.4-3.1ppm (q, 6H), 2.2 ppm (s, 3H), 1.8 ppm (s, 3H), 1.6-1.3 (m, 9H) and 1.0ppm (s, 3H).

EXAMPLE CLX6-(D-2-[2-carboxy-3-(2-thienyl)acrylamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To 20 ml. of water at ca. 0° C., is added 0.99 g. (5 mmole) of(2-thienyl)methylenemalonic acid followed by 1.86 g. (5 mmole) of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, andthe pH raised to 7.7. When a clear solution is obtained, the pH islowered to 6.0, and 0.96 g. (5 mmole) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide is added. The mixture isstirred at ca. 0° C. for 3 hours, with the pH being maintained at 6.0 bythe addition of 6 N hydrochloric acid. At this point, the pH is againraised to 7.7, and the reaction mixture is extracted with ethyl acetate.The extracts are discarded, and the residual aqueous phase is acidifiedto pH 2.6. The product is extracted into ethyl acetate, and then theextract is treated with 1.4 ml. (10 mmole) of triethylamine. The solventis removed by evaporation in vacuo, which affords 1.8 g. (55% yield) ofthe title compound as its triethylamine salt. IR (CHCl₃ solution): 1780,1660 and 1600 cm⁻¹. NMR (in CDCl₃): 11.6-10.9 ppm (s,1H), 8.5 ppm(s,1H), 7.8-6.9 ppm (m,9H), 5.9-5.3 ppm (m,4H), 1.6 ppm (s,3H), 1.0 ppm(s,3H).

In like manner, starting with (p-chlorophenyl)methylenemalonic acid,there is prepared, in 71% yield,6-(D-2-[2-carboxy-2-(p-chlorophenyl)acrylamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamtriethylamine salt. IR (KBr disc): 1780, 1670 and 1600 cm⁻¹. NMR (inCDCl₃): 10.5-9.0 ppm (m,1H), 8.1-7.1 ppm (m,10H), 5.9-5.3 ppm (m,4H),1.6 ppm (s,3H), 1.1 ppm (s,3H).

EXAMPLE CLXI6-(2,2-Dimethyl-5-oxo-4-phenyl-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam

A mixture of 1.0 g (2.34 mmole) of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,0.654 ml (4.86 mmole) of triethylamine and 100 ml of anhydrous acetoneis stirred at ca. 25° C. for 24 hours. At this point, the solvent isremoved by evaporation in vacuo, leaving 1.10 g of6-(2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,as its triethylamine salt. The infrared spectrum (KBr disc) showsabsorptions at 1786 cm⁻¹ (β-lactam) and 1709 cm⁻¹. The NMR spectrum(DMSO-d₆ /D₂ O) shows absorptions at 7.76-7.15 ppm (multiplet, 5H,aromatic hydrogens), 5.22 ppm (singlet, 1H, imidazolidine methinehydrogen) 5.78 and 5.10 ppm (two doublets, 2H, J=4 Hz, C-5 and C-6hydrogens), 4.69 ppm (singlet, 3H, C-3 hydrogen), 3.10 ppm (quarter, 6H, J=8 Hz, N--CH₂ --CH₃), 1.62 ppm (singlet, 3H, imidazolidine methylhydrogens), 1.50 ppm (singlet, 3H, C-2 methyl hydrogens), 1.40 ppm(singlet, 3H, imidazolidine methyl hydrogens), 1.21 ppm (triplet, 9H,J=8 Hz, N--CH₂ --CH₃) and 0.98 ppm (singlet, 3H, C-2 methyl hydrogens).

EXAMPLE CLXII6-(2,2-Dimethyl-5-oxo-4-[p-hydroxyphenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam

Reaction of6-(D-2-amino-2-[p-hydroxyphenyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,with acetone and triethylamine, according to the procedure of ExampleCLXI affords6-(2,2-dimethyl-5-oxo-4-[p-hydroxyphenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penamas its triethylamine salt. The infrared spectrum (KBr disc) showsabsorption bands at 1786 cm⁻¹ (β-lactam) and 1686 cm⁻¹. The NMR spectrum(DMSO-d₆ /D₂ O) shows absorptions at 6.82 and 7.35 ppm (quartet, 4H,aromatic hydrogens), 5.16 ppm (singlet, 1H, imidazolidine methinehydrogen), 5.71 and 5.07 ppm (two doublets, 2H, J=4 Hz, C-5 and C-6hydrogens), 4.52 ppm (singlet, 3H, C-3 hydrogen), 3.07 ppm (quartet, 6H,J=8 Hz, N--CH₂ --CH₃), 1.60 ppm (singlet, 3H, imidazolidine methylhydrogens), 1.43 ppm (singlet, 3H, C-2 methyl hydrogen), 1.36 ppm(singlet, 3H, imidazolidine methyl hydrogens), 1.16 ppm (triplet, 9H,J=8 Hz, N--CH₂ --CH₃) and 0.97 ppm (singlet, 3H, C-2 methyl hydrogens).

EXAMPLE CLXIII

Following the procedure of Example CLXI, and reacting the appropriate6-(2-amino-2-substituted-acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamwith the requisite aldehyde or ketone, the following compounds areprepared:

6-(2,2-dimethyl-5-oxo-4-[p-fluorophenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[o-chlorophenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[m-bromophenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-diethyl-5-oxo-4-[m-hydroxyphenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-ethyl-5-oxo-4-[p-hydroxyphenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[m-tolyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[p-amyloxyphenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[m-butoxyphenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[p-methoxyphenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-ethyl-2-methyl-5-oxo-4-[p-n-hexyloxyphenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[p-isopropylphenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[p-methylthiophenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-cyclopropyl-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-cyclopentyl-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-cyclohexyl-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-cycloheptyl-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[2-thienyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[3-thienyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[2-furyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[3-furyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[3-pyridyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,and

6-(2,2-dimethyl-5-oxo-4-[5-ethyl-2-thienyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[4-isothiazolyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[3-isothiazolyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[3-chloro-4-hydroxyphenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl(penam,

6-(2,2-dimethyl-5-oxo-4-[3,4-dimethoxyphenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2,2-dimethyl-5-oxo-4-[3-methyl-4-methoxyphenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam.

EXAMPLE CLXIV6-(5-Oxo-4-phenyl-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred suspension of 1.0 g. (2.26 mole) of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamtrihydrate in 15 ml. of water is added 151 μl. (2.53 mmole) of2-aminoethanol followed by 342 μl. (4.6 mmole) of 37% aqueousformaldehyde. The suspension is stirred for 7 hours, and then it islyophilized to give 0.96 g. (92% yield) of the title compound, as itsethanolamine salt. IR (KBr disc): 1773 cm⁻¹ (β-lactam) and 1681 cm⁻¹(amide I). NMR (in DMSO-d₆): 8.75 ppm (multiplet, 2H), 7.30 ppm(singlet, 5H), 6.00-5.60 ppm and 4.90-4.40 ppm (multiplets, 4H),4.00-3.20 ppm (multiplet, 4H), 1.70 ppm and 1.06 ppm (2 singlets, 6H).

EXAMPLE CLXV6-(5-Oxo-4-[p-hydroxyphenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam

The procedure of Example CLXIV is repeated, except that the6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamtrihydrate used therein is replaced by an equivalent amount of6-(D-2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamtrihydrate. This affords 0.96 g. (92% yield) of the title compound asits ethanolamine salt. IR (KBr disc): 1776 cm⁻¹ (β-lactam) and 1675 cm⁻¹(amide I). NMR (in DMSO-d₆): 8.52 ppm (multiplet, 2H), 7.14 ppm(multiplet, 4H), 5.90-5.00 ppm and 4.80-4.40 ppm (multiplets, 4H),3.80-3.00 ppm (multiplet, 4H), 1.67 ppm and 1.06 ppm (2 singlets, 6H).

EXAMPLE CLXVI

Following the procedure of Example CLXIV, and reacting the appropriate6-(2-amino-2-substituted-acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamwith the requisite aldehyde, the following compounds are prepared:

6-(5-oxo-4-[p-chlorophenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-methyl-5-oxo-4-[3-chloro-4-hydroxyphenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(5-oxo-4-[p-n-hexylphenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-methyl-5-oxo-[m-n-propylthiophenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penamand

6-(2-ethyl-5-oxo[p-n-hexylthiophenyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(5-oxo-4-[2-thienyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penamand

6-(5-oxo-4-[3-thienyl]-1-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam

respectively

EXAMPLE CLXVII6-([Hexahydro-1-azepinyl]methyleneamino)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 1.2 g (5 mmoles) of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 1.0 g (10 mmole) oftriethylamine and 30 ml of dichloromethane, cooled to 0° C., is added0.54 g (5 mmole) of chlorotrimethylsilane. After 15 minutes, 0.86 (5mmole) of 1-(dimethoxymethyl)hexahydroazepine (British Pat. No.1,293,590) is added, and stirring is continued for a further 1 hour. Thevolatile components are removed by evaporation in vacuo, and then theresidue is extracted with 25 ml of acetone. The insoluble material isfiltered off, and the acetone is evaporated in vacuo to a yellow foam,which changes to a white powder on trituration with ether. This affords1.44 g (82% yield) of6-([hexahydro-1-azepinyl]methyleneamino)-2,2-dimethyl-3-(5-tetrazolyl)penam.The infrared spectrum of the product (KBr disc) shows absorption bandsat 1795 cm⁻¹ (β-lactam), 1706 cm⁻¹ and 1645 cm⁻¹. The NMR spectrum(CDCl₃) shows absorption bands at 8.00 ppm (singlet, 1H, N--CH═N), 5.90and 5.60 ppm (two doublets, 2 H, J=4 Hz, C-5 and C-6 hydrogens), 5.40ppm (singlet, 1H, C-3 hydrogen), 3.90-3.50 (multiplet, 4H, CH₂--N--CH₂), 2.00-1.50 ppm (multiplet, 11H, C-2 methyl hydrogens and [CH₂]₄) and 1.20 ppm (singlet, 3H, C-2 methyl hydrogens). Examination of theproduct by thin-layer chromatography (0.2 M NaOAc: acetone; 1:6) showeda single spot (R_(f) 0.23).

EXAMPLE CLXVIII6-([Dimethylamino]methyleneamino)-2,2-dimethyl-3-(5-tetrazolyl)penam

Reaction of N,N-dimethylformamide dimethyl acetal with6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, according to the procedureof Example CLXVII on a 5 mmole scale produces 1.47 g (89% yield) ofproduct. The product is a 3:1 complex of6-([dimethylamino]methyleneamino)-2,2-dimethyl-3-(5-tetrazolyl)penamwith triethylamine. The infrared spectrum of the product (KBr disc)shows absorption bands at 1780 cm⁻¹ (β-lactam), 1710 cm⁻¹ and 1640 cm⁻¹.The NMR spectrum shows absorptions at 8.00 ppm (singlet, 1H, N--CH═N),5.80 and 5.50 ppm (two doublets, 2H, J=4 Hz, C-5 and C-6 hydrogens),5.30 ppm (singlet, 1H, C-3 hydrogen), 3.40-3.00 ppm (multiplet, 8H,N(CH₃)₂ and N--CH₂ --CH₃), 1.70 ppm (singlet, 3H, C-2 methyl hydrogens,1.30 ppm (triplet 3H, N--CH₂ --CH₃ ), 1.70 ppm (singlet, 3H, C-2 methylhydrogens). When examined by thin-layer chromatography (0.2 M NaOAc:acetone; 1:6), showed a single spot (R_(f) 0.26).

EXAMPLE CLXIX6-(D-2-[Dimethylaminomethyleneamino]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 3.73 g. (10 mmole) of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and2.02 g. (20 mmole) of triethylamine in 50 ml. of methylene chloride, at0° C., is added 1.08 g. (10 mmole) of trimethylsilyl chloride. Stirringis continued for 20 minutes at 0° C., and then 1.2 g. (10 mmole) ofN,N-dimethylformamide dimethyl acetal acetal is added. Stirring iscontinued for a further 2 hours, and then 2 ml. of methanol is added.The solvents are removed by evaporation in vacuo, and acetone is addedto the residue. After filtration, the filtrate is evaporated to dryness.This latter residue is dissolved in 25 ml. of methylene chloridecontaining 1.4 ml. of triethylamine, and then the solution is addeddropwise with stirring to 400 ml. of ether. The solid which precipitatesis filtered off, giving 4.83 g. (90% yield) of the title compound as itstriethylamine salt. IR (KBr disc): 1786, 1710 and 1652 cm⁻¹. NMR (in D₂O): 7.8 ppm (s, 1H), 7.6 ppm (s, 5H), 6.0 ppm (d, 2H), 5.8 ppm (d, 2H),5.5 ppm (s, 1H), 5.4 ppm (s, 1H), 3.3 ppm (q, 6H), 3.2 ppm (s, 6H), 1.8ppm (s, 3H), 1.4 ppm (t, 9H), and 1.2 ppm (s, 3H).

EXAMPLE CLXX6-(D-2-[2-(Hexahydro-1-azepinyl]methyleneamino)acetamido]acetamido)-2-dimethyl-3-(5-tetrazolyl)penam

A procedure analogous to that of Example CLXIX is used to obtain thetitle compound from the reaction 1.07 g. (2.5 mmol) of6-D-[2-(2-aminoacetamido)-2-phenylacetamido]-2,2-dimethyl-3-(5-tetrazolyl)penamand 0.43 g. (2.5 mmol) of 1-(dimethoxymethyl)hexahydroazepine. Theproduct is isolated as its triethylamine salt: yield 0.68 g (43%); IR(KBr) 1780 and 1695 cm⁻¹ ; NMR (D₂ O) 8.05 ppm (s, 1H), 7.75 (s, 5H),6.0-5.6 (m, 2H), 5.50 (s, 1H), 4.50 (s, 2H), 4.20 (s, 1H), 4.05-3.65 (m,4H), 3.4 (q, 6H), 2.35-1.75 (m, 8H), 1.70 (m, 8H), 1.70 (s, 3H), 1.55(t, 9H), 1.10 (s, 3H).

EXAMPLE CLXXI6-(D-2-[Dimethylaminomethyleneamino]-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 1.95 g. (5 mmole) of6-(D-2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamand 0.5 g. (5 mmole) of triethylamine in 12 ml. of methylene chloride,at 0° C., is added 0.6 g. of N,N-dimethylformamide dimethyl acetal.Stirring is continued for 1 hour at 0° C., and then the reaction mixtureis poured into 100 ml. of ether. This causes a gummy solid toprecipitate. The solvent is decanted from the solid, and then the solidis dissolved in 50 ml. of methylene chloride and 2 ml. of triethylamine.The solution is treated with activated charcoal, filtered, and thenadded dropwise to 100 ml. of ether. The solid which precipitates isredissolved in methylene chloride containing triethylamine, againtreated with activated charcoal, and again added dropwise with stirringto ether. The solid which precipitates is filtered off, giving 450 mg.(17% yield) of the title compound as its triethylamine salt. IR (KBrdisc): 1786, 1715 and 1652 cm⁻¹. NMR (in D₂ O-NaHCO₃): 7.7 ppm (s, 1H),7:3 ppm (d, 2H), 6.9 ppm (d, 2H), 5.8 ppm (d, 1H), 5.5 ppm (d, 1H), 5.3ppm (2s, 2H), 3.2 ppm (q, 6H), 3.1 ppm (s, 6H), 1.3 ppm (t, 9H), 1.0 ppm(s, 3H).

In like manner, starting with6-(D-2-[2-aminoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,there is prepared a 29% yield of a 2:1 complex of6-(D-2-[2-(dimethylaminomethyleneamino)acetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam-triethylamine.IR (KBr disc): 1780, 1715 and 1667 cm⁻¹. NMR (in D₂ O): 7.9 ppm (s, 1H),7.5 ppm (s, 5H), 5.6 ppm (s, 1H), 5.7 ppm (d, 1H), 5.5 ppm (d, 1H), 5.3ppm (s, 1H), 4.3 ppm (s, 2H), 3.3 ppm (s, 3H), 3.2 ppm (s, 3H), 3.2 (q,3H), 1.5 ppm (s, 3H), 1.3 ppm (t, 4.5H) and 1.0 ppm (s, 3H).

EXAMPLE CLXXII6-(2-Phenylacetamido)-2,2-dimethyl-3-(1-[pivaloyloxymethyl]tetrazol-5-yl)penamand6-(2-Phenylacetamido)-2,2-dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5-yl)penam

To a stirred suspension of 10.0 g. (0.0264 mole) of 6-(2 sodium salt, in105 ml. of acetone, is added 2.6 ml. of 25% aqueous sodium iodide,followed by 4.35 g. (0.0290 mole) of chloromethyl pivalate. The mixtureis refluxed for 4.5 hours, and then it is cooled to ambient temperature.To the mixture is then added 100 ml. of water, and the resultingsuspension is extracted with ethyl acetate. The extracts are dried andevaporated to give 6.3 g. of white foam. The MIC of this mixture of thetitle compounds against Strep. pyogenes in 0.2 μg/ml.

The white foam is re-dissolved in a small volume of 80:20chloroform-ethyl acetate and absorbed on a column of 180 g. ofchromatographic grade silica gel. The column is then eluted with 80:20chloroform-ethyl acetate taking fractions. Each fraction consists of 700drops of solvent. Fractions 55-95 are combined and evaporated in vacuoto give 2.03 g. of6-(2-phenylacetamido)-2,2-dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5-yl)penam.IR (KBr disc) 1785, 1760, 1670 and 1515 cm⁻¹. NMR (DMSO-d₆ /D₂ O): 7.50(s, 5H), 6.70 (s, 2H) 6.00-5.60 (m, 2H), 3.85 (s, 2H), 1.65 (s, 3H),1.36 (s, 9H) and 1.20 (s, 3H) ppm. Fractions 100-164 are combined andevaporated in vacuo to give 0.80 g. of6-(2-phenylacetamido)-2,2-dimethyl-3-(1-[pivaloyloxymethyl]tetrazol-5-yl)penam.IR (KBr disc): 1780, 1760, 1670 and 1515 cm⁻¹. NMR (DMSO-d₆ (D₂ O): 7.50(s, 5H) 6.80 (s, 2H), 6.50 (s, 2H), 5.60 (s, 1H), 3.85 (s, 2H), 1.75 (s,3H), 1.36 (s, 9H) and 1.34 (s, 3H) ppm.

Reaction of 6-(2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamsodium salt with 1-acetoxyethyl chloride, according to the aboveprocedure, produces6-(2-phenylacetamido)-2,2-dimethyl-3-(1[2]-[1-acetoxyethyl]tetrazol-5-yl)penamas a mixture of isomers, m.p. 55°-70° C., yield 28%. IR (KBr disc):1780, 1770, 1670 and 1515 cm⁻¹. NMR (CDCl₃): 7.20 (s, 6H), 6.25 (m, 1H),5.75-5.40 (m, 2H), 5.20 (s, 1H), 3.60 (s, 2H), 2.00 (m, 6H), 1.45 (s,3H) and 0.95 (s, 3H) ppm.

In like manner, reaction of6-(2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam sodium saltwith 3-bromophthalide, according to the above procedure, produces6-(2-phenylacetamido)-2,2-dimethyl-3-(1[2]-[3-phthalidyl]tetrazol-5-yl)penamas a mixture of isomers, m.p. 70°-85° C., yield 91%. IR (KBr disc):1785, 1675 and 1500 cm⁻¹. NMR (CDCl₃): 8.05-7.10 (m, 9H), 6.55-6.20 (m,2H), 5.80 (m, 2H), 5.20 (m, 1H), 3.60 (s, 2H), 1.60 (s, 3H) and 1.00 (s,3H) ppm.

EXAMPLE CLXXIII

Reaction of the appropriate6-acylamino-2,2-dimethyl-3-(5-tetrazolyl)penam with the requisitealkanoyloxyalkyl chloride or with 3-bromophthalide, according to theprocedure of Example CLXXII, provides the following congeners. In eachcase, the product is a mixture of monoalkylated compounds, in which thealkanoyloxyalkyl or phthalidyl substituent is located at either the 1-or the 2-position of the tetrazole ring.

6-acetamido-2,2-dimethyl-3-(1[2]-acetoxymethyltetrazol-5-yl)penam,

6-propionamido-2,2-dimethyl-3-(1-[2]-isobutyryloxymethyltetrazol-5-yl)penam

6-(2-phenylacetamido)-2,2-dimethyl-3-(1[2]-propionyloxymethyltetrazol-5-yl)penam,

6-(2-phenoxyacetamido)-2,2-dimethyl-3-(1[2]-n-hexanoyloxymethyltetrazol-5-yl)penam,

6-(2-cyclohexanecarboxamido)-2,2-dimethyl-3-(1[2]-pivaloyloxymethyltetrazol-5-yl)penam,

6-(2-p-chlorophenylacetamido)-2,2-dimethyl-3-(1[2]-acetoxymethyltetrazol-5-yl)penam,

6-(2-m-methoxyphenylacetamido)-2,2-dimethyl-3-(1[2]-propionyloxymethyltetrazol-5-yl)penam,

6-(2-[3-chloro-4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(1[2]-pivaloyloxymethyltetrazol-5-yl)penam

6-(2-[2-thienyl]acetamido)-2,2-dimethyl-3-(1-[2]-acetoxymethyltetrazol-5-yl)penam

6-(3-furancarboxamido)-2,2-dimethyl-3-(1-[2]-n-butyryloxymethyltetrazol-5-yl)penam,

6-(2-phenylpropionamido)-2,2-dimethyl-3-(1-[2]-pivaloyloxymethyltetrazol-5-yl)penam,

6-(2-phenoxyacetamido)-2,2-dimethyl-3-(1[2]-pivaloyloxymethyltetrazol-5-yl)penam,

6-acetamido-2,2-dimethyl-3-(1[2]-[1-acetoxymethyl]tetrazol-5-yl)penam,

6-(2-cyclohexylacetamido)-2,2-dimethyl-3-(1[2]-[1-propionyloxyethyl]tetrazol-5-yl)penam,

6-(2-phenylacetamido)-2,2-dimethyl-3-(1[2]-[1-pivaloyloxyethyl]tetrazol-5-yl)penam,

6-(2-phenoxyacetamido)-2,2-dimethyl-3-(1[2]-[1-n-hexanoyloxyethyl]tetrazolyl)penam,

6-(2-[3-thienyl]acetamido)-2,2-dimethyl-3-(1-[2]-[1-acetoxyethyl]tetrazolyl)penam,

6-propionamido-2,2-dimethyl-3-(1[2]-phthalidyltetrazol-5-yl)penam

6-(2-phenylacetamido)-2,2-dimethyl-3-(1-[2]-phthalidyltetrazol-5-yl)penam,

6-(2-phenoxyacetamido)-2,2-dimethyl-3-(1[2]-phthalidyltetrazol-5-yl)penam,

6-(2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(1[2]-phthalidyltetrazol-5-yl)penam,

6-(2-[2-furyl]acetamido)-2,2-dimethyl-3-(1[2]-phthalidyltetrazol-5-yl)penamand

6-(2-[5-methyl-2-thienyl]acetamido)-2,2-dimethyl-3-(1[2]-phthalidyltetrazol-5-yl)penam,

respectively.

EXAMPLE CLXXIV6-(2-[2-Azidomethylphenyl]acetamido)-2,2-dimethyl-3-(1-[2]-pivaloyloxymethyltetrazol-5-yl)penam

A solution of 5.0 g. of6-(2-[2-azidomethylphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,1.9 g. of chloromethylpivalate, 50 ml. of acetone and 1.25 ml. of a 25%solution of sodium iodide in water is heated under reflux for 4 hours.The mixture is cooled, 100 ml. of water is added and the mixture isextracted with ethyl acetate. The extract is dried and evaporated,yielding 4.9 g. (83% yield) of the title compound, as a mixture ofisomers as indicated. IR(CHCl₃): 2110, 1790, 1769, 1685 and 1510 cm.⁻¹NMR (CDCl₃): 7.40 (2s, 4H), 6.45 and 6.35 (2s, 2H), 5.70 (m, 2H), 5.50and 5.30 (2s, 1H), 4.50 (s, 2H), 3.72 (s, 2H), 1.63 and 1.55 (2s, 3H),1.23 (s, 9H) and 1.06 ppm (s, 3H).

EXAMPLE CLXXV6-(2-[2-Aminomethylphenyl]acetamido)-2,2-dimethyl-3-(1-[2]-pivaloyloxymethyltetrazol-5-yl)penam

To a solution of 4.0 g. of6-(2-[2-azidomethylphenyl]acetamido)-2,2-dimethyl-3-(1-[2]-pivaloyloxymethyltetrazol-5-yl)penamin 60 ml. of ethyl acetate is added 60 ml. of water, followed by 2 g. of10% palladium-on-carbon. The two-phase system is stirred rapidly whilehydrogen is bubbled through, and the pH is maintained at 3.0-3.5 byaddition of dilute hydrochloric acid. Reaction is allowed to proceed inthis manner for 4 hours, and then the catalyst is removed by filtration.The layers are separated, the ethyl acetate is washed with water, andthe combined aqueous layers are lyophilized. This affords a mixture ofthe title compounds as their hydrochloride salts: yield 2.2 g (54%). IR(KBr disc): 1790, 1760, 1645 and 1550 cm.⁻¹ NMR (DMSO-d₆ /D₂ O): 7.46(s, 4H), 6.65 (s, 2H), 5.7-5.5 (m, 2H), 5.38 (s, 1H), 4.20 (s, 2H), 3.83(s, 2H), 1.77 and 1.73 (2s, 3H), 1.20 (s, 9H) and 1.06 (s, 3H).

EXAMPLE CLXXVI6-Amino-2,2-dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5-yl)penam

To a stirred solution of 0.932 g. (7.21 m mole) of quinoline in 8.0 ml.of chloroform is added 0.840 g. (4.05 m mole) of phosphoruspentachloride. The suspension is cooled to -15° C., and then 1.81 g.(3.84 m mole) of6-(2-phenylacetamido)-2,2-dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5-yl)penamis added. Stirring is continued for a further 30 minutes, at ca. -5° C.,and then 2.15 g. (35.7 m mole) of n-propanol is added. Stirring iscontinued for a further 30 minutes, again at ca. -5° C., and then 25 ml.of 90:10 isopropyl ether-acetone is added, followed immediately by asolution of 1.35 g. of sodium chloride in 6.02 ml. of water. Thetemperature rises to 15° C. and then it is lowered again to -15° C. Theprecipitate which has formed is filtered off and dried, giving 1.33 g.(88% yield) of6-amino-2,2-dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5-yl)penamhydrochloride. The infrared spectrum (KBr disc) shows absorptions at1785 cm⁻¹ (β-lactam) and 1750 cm⁻¹ (ester). The NMR spectrum (DMSO-d₆)shows absorptions at 6.70 ppm (singlet, 2H, pivaloyloxy methylenehydrogens), 5.75 ppm (doublet, 1H, C-5 hydrogen), 5.50 ppm (singlet, 1H,C-3 hydrogen), 5.70 ppm (doublet, 1H, C-6 hydrogen), 1.75 ppm (singlet,3H, C-2 methyl hydrogens), 1.20 ppm (singlet, 9H, t-butyl hydrogens) and1.10 ppm (singlet, 3H, C-2 methyl hydrogens).

EXAMPLE CLXXVII6-Amino-2,2-dimethyl-3-(1-[pivaloyloxymethyl]tetrazol-5-yl)penam

The title compound is prepared as its hydrochloride, in 90% yield, from6-(2-phenylacetamido)-2,2-dimethyl-3-(1-[pivaloyloxymethyl]tetrazol-5-yl)penam,using the method of Example CLXXVI. The infrared spectrum (KBr disc)shows absorptions at 1780 cm⁻¹ (β-lactam) and 1740 cm⁻¹ (ester). The NMRspectrum (DMSO-d₆) shows absorptions at 6.71 ppm (singlet, 2H,pivaloyloxy methylene hydrogens), 5.88 ppm (singlet, 1H, C-3 hydrogen),5.83 ppm (doublet, 1H, C-5 hydrogen), 5.20 ppm (doublet, 1H, C-6hydrogen), 1.80 ppm (singlet, 3H, C-2 methyl hydrogens), 1.20 ppm(singlet, 9H, t-butyl hydrogens) and 1.16 ppm (singlet, 3H, C-2 methylhydrogens).

EXAMPLE CLXXVIII

Using the procedure of Example CLXXVI, and utilizing as startingmaterial an appropriate 6-acylamino-2,2-dimethyl-3-(1[2]-substitutedtetrazol-5-yl)penam chosen from those in Example CLXXIII, the followingcompounds are prepared:

6-amino-2,2-dimethyl-3-(1[2]-acetoxymethyltetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1[2]-isobutyryloxymethyltetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1[2]-propionoxymethyltetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1[2]-n-hexanoyloxymethyltetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1-[2]-[1-acetoxyethyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1[2]-[1-propionyloxyethyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1[2]-[1-pivaloyloxyethyl]tetrazol-5-yl)penam,

6-amino-2,2-dimethyl-3-(1[2]-[1-n-hexanoyloxymethyl]tetrazol-5-yl)penamand

6-amino-2,2-dimethyl-3-(1[2]-phthalidyltetrazol-5-yl)penam,

respectively.

EXAMPLE CLXXIX6-(D-2-Amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5-yl)penam

To a stirred suspension of 287 mg. (1.0 m mole) of sodiumN-(2-methoxycarbonyl-1-methylvinyl)-D-2-amino-2-(p-hydroxyphenyl)acetate(Long, et. al., Journal of the Chemical Society [London], Part C, 1920[1971]) and 1 drop of N-methylmorpholine in 6 ml. of ethyl acetate, isadded 0.97 ml. (1.03 mole) of ethylchloroformate, at -15° C. Stirring iscontinued for a further 30 minutes at -15° C. This mixture is then addedto a pre-cooled (-15° C.) suspension of 390.5 mg. (1.0 m mole) of6-amino-2,2-dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5-yl)penamhydrochloride in 2 ml. of ethyl acetate containing 101 mg. (1.0 m mole)of triethylamine. The reaction mixture is then stirred at -15° C. for 1hour followed by 5° C. for 1 hour. The ethyl acetate is removed byevaporation in vacuo, and the white solid thus obtained is suspended in10 ml. of 1:1 water-tetrahydrofuran. The suspension is cooled to 0° C.,and then its pH is adjusted to 2.1. The suspension is stirred at 0° C.for 45 minutes, with further acid being added to maintain the pH at 2.1as necessary. At this point, the tetrahydrofuran is removed byevaporation in vacuo, the residual aqueous phase is saturated withsodium chloride, and the product is extracted into ethyl acetate. Theethyl acetate is dried and evaporated in vacuo giving after triturationof the residue with ether, 425 mg. (81% yield) of6-(D-2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5-yl)penamhydrochloride. The infrared spectrum (KBr disc) shows absorptions at1780 cm⁻¹ (β-lactam) 1755 cm⁻¹ (ester), 1682 cm⁻¹ (amide I). The NMRspectrum (DMSO-d₆) shows absorptions at 7.09 ppm (quartet, 4H, aromatichydrogens), 6.59 ppm (singlet, 2H, pivaloyloxy methylene), 5.52 ppm(multiplet 2H, C-5 and C-6 hydrogens), 5.22 ppm (singlet, 1H, side chainmethine hydrogen) 5.00 ppm (singlet, 1H, C-3 hydrogen), 1.47 ppm(singlet, 3H, C-2 methyl hydrogen), 1.07 ppm (singlet, 9H, t-butylhydrogens), and 0.96 ppm (singlet, 3H, C-2 methyl hydrogens).

The MIC of the title compound against Strep. pyogenes is 0.39 μg./ml.

EXAMPLE CLXXX6-(D-2-Amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(1-[pivaloyloxymethyl]tetrazol-5-yl)penam

The title compound is prepared as its hydrochloride, in 50% yield, from6-amino-2,2-dimethyl-3-(1-[pivaloyloxymethyl]tetrazol-5-yl)penam, usingthe procedure of Example CLXXIX. The infrared spectrum of the product(KBr disc) shows absorptions at 1780 cm⁻¹ (β-lactam) and 1680 cm⁻¹(amide I). The NMR spectrum (DMSO-d₆) shows absorptions at 7.09 ppm(quartet, 4H, aromatic hydrogens), 6.55 ppm (singlet, 2H, pivaloyloxymethylene hydrogens), 5.61 ppm (multiplet, 3H, C-3, C-5 and C-6hydrogens), 5.06 ppm (singlet, 1H, side-chain methine hydrogen), 1.55ppm (singlet, 3H, C-2 methyl hydrogen), 1.10 ppm (singlet, 3H, C-2methyl hydrogen), 1.10 ppm (singlet, 9H, t-butyl hydrogens) and 1.03 ppm(singlet, 3H, C-2 methyl hydrogens).

EXAMPLE CLXXXI

Using the procedure of Example CLXXIX, reaction of the appropriate6-amino-2,2-dimethyl-3-(pivaloyloxymethyltetrazol-5-yl)penam with therequisite sodiumN-(2-methoxycarbonyl-1-methylvinyl)-2-amino-2-substituted acetateprovides the following compounds:

6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(1-pivaloyloxymethyltetrazol-5-yl)penam,

6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(2-pivaloyloxymethyltetrazol-5-yl)penam,

6-(D-2-amino-2-[2-thienyl]acetamido)-2,2-dimethyl-3-(2-pivaloyloxymethyltetrazol-5-yl)penam

6-(D-2-amino-2-[3-chloro-4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(2-pivaloyloxymethyltetrazol-5-yl)penamand

6-(D-2-amino-2-[3-thienyl]acetamido)-2,2-dimethyl-3-2-pivaloyloxymethyltetrazol-5-yl)penam,

respectively.

EXAMPLE CLXXXII6-(D-2-[3-(2-Furoyl)ureido]-2-phenylacetamido)-2,2-dimethyl-3-(1-pivaloyloxymethyltetrazol-5-yl)penam

To a stirred solution of 455 mg. of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(1-pivaloyloxymethyltetrazol-5-yl)penamin 20 ml. of methylene chloride, at 0° C., is added 137 mg. of 2-furoylisocyanate dissolved in 5 ml. of methylene chloride. The cooling bath isthen removed, and stirring is continued for 2 hours. The solvent isremoved in vacuo to give the title compound.

EXAMPLE CLXXXIII

The procedure of Example CLXXXII, is repeated, except the6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(1-pivaloyloxymethyltetrazol-5-yl)penamused therein is replaced by the appropriate 6-(D-2-amino-2-substitutedacetamido)-2,2-dimethyl-3-(1[2]-substituted tetrazol-5-yl)penam, and the2-furoyl isocyanate is replaced by the requisite isocyanate. Thisaffords:

6-(D-2-[3-(3-furoyl)ureido]-2-phenylacetamido)-2,2-dimethyl-3-(1-[1-acetoxy)ethyl]tetrazol-5-yl)penam,

6-(D-2-[3-benzoylureido]-2-[2-thienyl]acetamido)-2,2-dimethyl-3-(2-pivaloyloxymethyl]tetrazol-5-yl)penamand

6-(D-2-[3-(3-thienyl)ureido]-2-[3-chloro-4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(2-pivaloyloxymethyl]tetrazol-5-yl)penam,

respectively.

EXAMPLE CLXXXIV

Reaction of the appropriate 6-(2-amino-2-substitutedacetamido)-2,2-dimethyl-3-(substituted tetrazol-5-yl)penam compound withthe requisite aldehyde or ketone, according to the procedure of ExampleCLXI, produces the following compounds:

6-(2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl)-2,2-dimethyl-3-(1-[pivaloyloxymethyl]tetrazol-5-yl)penam,

6-(2,2-dimethyl-5-oxo-4-[4-hydroxyphenyl]-1-imidazolindinyl)-2,2-dimethyl-3-(1-[acetoxymethyl]tetrazol-5-yl)penam,

6-(2-methyl-5-oxo-4-[2-thienyl]-1-imidazolindinyl)-2,2-dimethyl-3-(1-[n-hexanoyloxymethyl]tetrazol-5-yl)penam,

6-(2,2-dimethyl-5-oxo-4-[3-chloro-4-hydroxyphenyl]imidazolindinyl)-2,2-dimethyl-3-(1-[1-(acetoxy)ethyl]tetrazol-5-yl)penam,

6-(2,2-diethyl-5-oxo-4-[3-thienyl]-1-imidazolidinyl)-2,2-dimethyl-3-(1-[1-(n-hexanoyloxy)ethyl]tetrazol-5-yl)penam,

6-(2,2-dimethyl-5-oxo-4-phenyl-1-imidazolindinyl)-2,2-dimethyl-3-(1-phthalidyltetrazol-5-yl)penamand

6-(2,2-dimethyl-5-oxo-4-phenyl-1-imidazolindinyl)-2,2-dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5-yl)penam,

respectively.

EXAMPLE CLXXXV6-(Triphenylmethylamino)-2,2-dimethyl-3-(1[2]-pivaloyloxymethyltetrazol-5-yl)penam

To a stirred solution of 932 mg. of6-(triphenylmethylamino)-2,2-dimethyl-3-(5-tetrazolyl)penam and 0.28 ml.of triethylamine in 10 ml. of dimethylformamide, at 0° C. is added 301mg. of chloromethyl pivalate. The cooling bath is removed after 15minutes and the reaction mixture is stirred at ambient temperature for 2hours. At this point the solvent is removed by evaporation under highvacuum and to the residue is added water and ethyl acetate. The pH isadjusted to 7.0, and the water is removed and discarded. The ethylacetate is washed with water, dried using anhydrous sodium sulfate andevaporated to dryness in vacuo. This affords the title product as amixture of isomers as indicated. The individual isomers can be obtainedby chromatography.

EXAMPLE CLXXXVI6-Amino-2,2-dimethyl-3-(1[2]-pivaloyloxymethyltetrazol-5-yl)penam

The title product is prepared as its p-toluenesulfonate salt, bytreating6-(triphenylmethylamino)-2,2-dimethyl-3-(1[2]-pivaloyloxytetrazol-5-yl)penamwith p-toluenesulfonic acid in acetone, according to the procedure ofExample XX.

EXAMPLE CLXXXVII6-Amino-2,2-dimethyl-3-(1-pivaloyloxymethyltetrazol-5-yl)penam and6-Amino-2,2-dimethyl-3-(2-pivaloyloxymethyltetrazol-5-yl)penam

To a stirred suspension of 2.40 g. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 15 ml. ofN,N-dimethylformamide, is added 2.8 ml. of triethylamine. Stirring iscontinued for a further 15 minutes, and then 2.68 g. of chloromethylpivalate is added. The mixture is stirred at ambient temperature for 5hours, and then it is diluted with 100 ml. of water. It is thenextracted with ethyl acetate. The extract is washed with water, driedusing anhydrous sodium sulfate, and then it is evaporated in vacuo togive a mixture of the title compounds. The individual isomers areobtained by chromatographic separation of the crude product.

EXAMPLE CLXXXVIII6-(2-Phenylacetamido)-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam

To a stirred solution of 189 mg of6-amino-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam in 4 mlof chloroform, is added, at ambient temperature, 0.038 ml of pyridinefollowed by 0.057 ml of phenylacetyl chloride. Stirring is continued fora further 45 minutes, and then the reaction mixture is diluted with 25ml of chloroform and then washed with water. The organic phase is driedusing anhydrous magnesium sulfate and then evaporated in vacuo. Theresidue is 209 mg (86% yield) of6-(2-phenylacetamido)-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam.The NMR spectrum (in CDCl₃) shows absorptions at 7.50-6.70 ppm(multiplet, aromatic hydrogens), 6.4 ppm (doublet, amide hydrogen),5.80-5.20 ppm (multiplet, benzyl hydrogens and C-5 and C-6 hydrogens),5.10 ppm (singlet, C-3 hydrogen), 5.05 ppm (singlet, benzyl hydrogens),3.60 ppm (singlet, phenylacetyl methylene hydrogens), 1.30 ppm (singlet,C-2 methyl hydrogens) and 0.85 ppm (singlet, C-2 methyl hydrogens).

EXAMPLE CLXXXIX

Reaction of the appropriate 6-amino-2,2-dimethyl-3-(1-substitutedtetrazol-5-yl)penam with the requisite acid chloride, according to theprocedure of Example CLXXXVIII provides the following compounds:

    ______________________________________                                         ##STR58##                                                                      R.sup.1          R.sup.2                                                    ______________________________________                                        acetyl                p-methoxy-benzyl                                        acetyl                m-ethoxybenzyl                                          acroloyl              p-benzyloxybenzyl                                       cyclohexanecarbonyl   benzyl                                                  benzoyl               2-furylmethyl                                           p-chlorobenzoyl       3-furylmethyl                                           o-flourobenzoyl       p-isopropoxybenzyl                                      2-phenylacetyl        p-hydroxybenzyl                                         3-phenylpropionyl     p-methoxybenzyl                                         2-(p-tolyl)acetyl     o-methoxybenzyl                                         2-(p-(isopropylphenyl)acetyl                                                                        2-furylmethylbenzyl                                     2-(m-chlorophenyl)acetyl                                                                            p-n-butoxybenzyl                                        2-(3,5-dibromophenyl)acetyl                                                                         pivaloyloxymethyl                                       2-(p-chlorophenoxy)acetyl                                                                           p-methoxybenzyl                                         2-thienylcarbonyl     o-methoxybenzyl                                         2-(3-thienyl)acetyl   p-methoxybenzyl                                         2-(2-furyl)acetyl     p-hydroxybenzyl                                         2-(3-pyridyl)acetyl   p-n-hexyloxybenzyl                                      2-(5-tetrazolyl)acetyl                                                                              2-furylmethyl                                           2-azido-2-phenylacetyl                                                                              p-methoxybenzyl                                         2-(p-cyanophenyl)acetyl                                                                             p-benzyloxybenzyl                                       dodecanoyl            p-methoxybenzyl                                         acryloyl              p-ethoxybenzyl                                          Δ.sup.2 -octenoyl                                                                             o-methoxybenzyl                                         Δ.sup.11 -undecenoyl                                                                          m-methoxybenzyl                                         Δ.sup.12 -dodecenoyl                                                                          2-furylmethyl                                           2-(phenylthio)acetyl  p-methoxybenzyl                                         2-phenylacetyl        4-phenylbenzyl                                          2-phenoxyacetyl       3-chlorobenzyl                                          2-phenoxyacetyl       3-chloro-4-methoxybenzyl                                2-(2-thienyl)acetyl   2,4-dimethoxybenzyl                                     2-(3-thienyl)acetyl   4-n-hexylbenzyl                                         2,6-diethoxybenzoyl   4-flourobenzyl                                          2-2(thienyl)acetyl    3,4-dimethoxybenzyl                                     2-n-butoxy-1-naphthoyl                                                                              4-nitrobenzyl                                           2-cycloheptylacetyl   3,5-dichlorobenzyl                                      2-(cyclohex-3-enyl)acetyl                                                                           3-chloro-4-ethoxybenzyl                                 3-phenylpropionyl     4-isopropylbenzyl                                       2-phenylthioacetyl    4-iodobenzyl                                            2-(1-pyrazolyl)acetyl 4-n-hexylbenzyl                                         2-(1-pyrrolyl)acetyl  4-n-hexyloxybenzyl                                      2-(1,2,4-triazol-1-yl)acetyl                                                                        4-biphenylylmethyl                                      2-(3-sydnonyl)acetyl  4-bromophenyl                                           2-bromoacetyl         4-ethylbenzyl                                           2-phenylacetyl        4-(n-hexyloxymethoxy)benzyl                             2-phenoxyacetyl       4-(2-chlorophenyl)benzyl                                2-(3-thienyl)acetyl   4-(4-tolyl)benzyl                                       2-(3-chlorophenyl)acetyl                                                                            2-(4-methoxyphenyl)benzyl                               2-phenylacetyl        COOC.sub.2 H.sub.5                                      2-phenylbutyryl       COOCH.sub.3                                             2-phenoxyacetyl       COOC.sub.2 H.sub.5                                      2-phenylthioacetyl    COO-n-C.sub.6 H.sub.3                                   2-thienylacetyl       COOCH.sub.2 C.sub.6 H.sub.5                             3-thienylacetyl       COOC.sub.6 H.sub.5                                      3-thienylacetyl       COO-[4-(n-C.sub.4 H.sub.9)C.sub.6 H.sub.4 ]             2-bromoacetyl         COO-[4-NO.sub.2 C .sub.6 H.sub.4 ]                      2-chloracetyl         COO-(3-BrC.sub.6 H.sub.4)                               4-bromobutyryl        COO-[4-(i-C.sub.3 H.sub.7 O)C.sub.6 H.sub.4 ]           2-(4-fluorophenyl)acetyl                                                                            COO-(2,4-Cl.sub.2 C.sub.6 H.sub.3)                      phenoxycarbonyl       COO-(2-CH.sub.3 OC.sub.6 H.sub.4)                       benzyloxycarbonyl     COO[4- (n-C.sub.6 H.sub.13 O)C.sub.6 H.sub.3 ]          2-(4-fluorophenyl)acetyl                                                                            COO-(2-FC.sub.6 H.sub.4)                                2,6-diethoxybenzoyl   COO-(2-CH.sub.3 C.sub.6 H.sub.4)                        2-(4-pyridylthio)acetyl                                                                             COO-[4-(t-C.sub.4 H.sub.9)C.sub.6 H.sub.4 ]             5-methyl-3-phenyl-4-  COO-[2,4-(NO.sub.2).sub.2 C.sub.6 H.sub.3 ]             isoxazolyl carbonyl                                                           2-cyanoacetyl         COOCH.sub.3                                             2-(5-tetrazolyl)acetyl                                                                              COOC.sub.2 H.sub.5                                      2-(1-tetrazolyl)acetyl                                                                              COO-n-C.sub.4 H.sub.9                                   2-azido-2-phenylacetyl                                                                              COOCH.sub.2 C.sub.6 H.sub.5                             2-sulfo-2-phenylacetyl                                                                              COO-[2-NO.sub.2 -4-(C.sub.3 H.sub.7 O)C.sub.6                                 H.sub.3 ]                                               4-methyl-1-(2,6-dichloro-                                                     phenyl)-5-pyrazolylcarbonyl                                                                         COOC.sub.2 H.sub.5                                      Δ.sup.12 dodecenoyl                                                                           COOCH.sub.2 C.sub.6 H.sub.5                             acryloyl              COOC.sub.6 H.sub.5                                      cyclbutylcarbonyl     COOC.sub.2 H.sub.5                                      2-phenylacetyl        SO.sub.2 CH.sub.3                                       2-phenoxyacetyl       SO.sub.2 CH.sub.2 (CH.sub.2).sub.4 CH.sub.3             2-(3-thienyl)acetyl   SO.sub.2 CH.sub.2 C.sub.6 H.sub.5                       2-cyanoacetyl         SO.sub.2 C.sub.6 H.sub.5                                2-(2-fluorophenyl)acetyl                                                                            SO.sub.2 -[4-NO.sub.2)C.sub.6 H.sub.4 ]                 2-(3,4-dichlorophenyl)acetyl                                                                        SO.sub.2 -(4-BrC.sub.6 H.sub.4)                         2-(3-bromophenyl)acetyl                                                                             SO.sub.2 -(2-ClC.sub.6 H.sub.4)                         2-(3-tolyl)acetyl     SO.sub.2 -[2-C.sub.2 H.sub.5)C.sub.6 H.sub.4)           2-(4-isopropylphenyl)acetyl                                                                         SO.sub.2 -[3-(n-C.sub.4 H.sub.9)C.sub.6 H.sub.4 ]       2-(4-amyloxyphenyl)acetyl                                                                           SO.sub.2 -[4-(CH.sub.3 O)C.sub.6 H.sub.4]               acryloyl              SO.sub.2 -(2,4-Cl.sub.2 C.sub.6 H.sub.3)                2-(4-cyanophenyl)acetyl                                                                             SO.sub.2 -[3-CH.sub.3-4- (CH.sub.3 O)C.sub.6                                  H.sub.3]                                                2-(2-furyl)acetyl     SO.sub.2 -[2,4-(NO.sub.2).sub.2 C.sub.6 H.sub.3 ]       ethoxycarbonyl        SO.sub.2 -[2-CH.sub.3 O-5-(NO.sub.2)C.sub.6                                   H.sub.3]                                                acetyl                SO.sub.2 -CH.sub.2 -(4-ClC.sub.6 H.sub.4)               butyryl               SO.sub.2 -CH.sub.2 -(2-BrC.sub.6 H.sub.4)               benzoyl               SO.sub.2 CH.sub.2 -(3-CH.sub.3 C.sub.6 H.sub.4)         cyclopentanecarbonyl  SO.sub.2 C.sub.2 H.sub.5                                1,4-cyclohexadienylcarbonyl                                                                         SO.sub.2 C.sub.2 H.sub.5                                2-(2-tetrazolyl)acetyl                                                                              SO.sub.2 -[4-(n-C.sub.4 H.sub.9 O)C.sub.6 H.sub.4                             ]                                                       2-(4-chlorophenyl)thioacetyl                                                                        SO.sub.2 C.sub.6 H.sub.5                                2-phenylacetyl        phthalidyl                                              2-(2-thienyl)acetyl    "                                                      2-(3-thienyl)acetyl    "                                                      2-phenoxyacetyl        "                                                      2-bromoacetyl          "                                                      1,4-cyclohexadienylcarbonyl                                                                          "                                                      ______________________________________                                    

EXAMPLE CXC

Reaction of the appropriate 6-amino-2,2-dimethyl-3-(1-substitutedtetrazol-5-yl)penam with the requisite sodiumN-(2-methoxycarbonyl-1-methylvinyl)-2-amino-2-substituted acetate,according to the procedure of Example CLXXIX, affords the followingcongeners:

    ______________________________________                                         ##STR59##                                                                     R.sup.7          R.sup.2                                                     ______________________________________                                        methyl           p-methoxybenzyl                                              isopropyl        p-hydroxybenzyl                                              cyclopentyl      p-methoxybenzyl                                              phenyl           m-ethoxybenzyl                                               phenyl           p-methoxybenzyl                                              phenyl           phenyl                                                       phenyl           2-furylmethyl                                                phenyl           p-methoxybenzyl                                              p-hydroxyphenyl  p-methoxybenzyl                                              p-hydroxyphenyl  p-hydroxybenzyl                                              3-chloro-4-hydroxyphenyl                                                                       2-furylmethyl                                                2-thienyl        p-methoxybenzyl                                              3-thienyl        p-hydroxybenzyl                                              2-furyl          2-furylmethyl                                                4-methoxyphenyl  3-chloro-4-methoxybenzyl                                     4-N,N-dimethylaminophenyl                                                                      3-chloroenzyl                                                3-pyridyl        4-benzyloxybenzyl                                            phenyl           4-phenylbenzyl                                               benzyl           2,4-dimethoxybenzyl                                          3-indolylmethyl  4-iodobenzyl                                                 2,4-dichlorophenyl                                                                             4-n-hexylbenzyl                                              3-tolylphenyl    4-bromophenyl                                                2-methoxyphenyl  4-ethylbenzyl                                                3,5-dimethoxyphenyl                                                                            4-biphenylmethyl                                             4-methylthiophenyl                                                                             1-(4-methoxyphenyl)ethyl                                     3-furyl          4-nitrobenzyl                                                4-methylthiophenyl                                                                             2-fluorobenzyl                                               cyclohexyl       4-methoxybenzyl                                              phenyl           COOC.sub.2 H.sub.5                                           3-thienyl        COOC.sub.2 H.sub.5                                           1,4-cyclohexadienyl                                                                            COOC.sub.2 H.sub.5                                           p-hydroxyphenyl  COOCH.sub.3                                                  3-chloro-4-hydroxyphenyl                                                                       COOC.sub.2 H.sub.5                                           phenyl           COOC.sub.6 H.sub.13                                          phenyl           COOC.sub.6 H.sub.5                                           4-chlorophenyl   COOCH.sub.2 C.sub.6 H.sub.5                                  cyclohexyl       COO-[4-(CH.sub.3)C.sub.6 H.sub.4 ]                           3-thienyl        COO-[2-(CH.sub.3 O)C.sub.6 H.sub.4 ]                         phenyl           COO-[2-NO.sub.2 -4-(C.sub.3 H.sub.7 O)C.sub.6 H.sub.3 ]                       N                                                            methyl           COO-[2,4-(NO.sub.2).sub.2 C.sub.6 H.sub.3 ]                  n-octyl          COO-(2-FC.sub.6 H.sub.4 ]                                    cyclopropyl      COO-(3-BrC.sub.6 H.sub.4)                                    Δ.sup.2 -prophenyl                                                                       COO-[4-(n-C.sub.4 H.sub.9)C.sub.6 H.sub.4 ]                  Δ.sup.2 -butenyl                                                                         COO-[4-Cl-3-CH.sub.3 C.sub.6 H.sub.3 ]                       5-ethyl-2-thienyl                                                                              COO-COO-i-C.sub.3 H.sub.7                                    4-dimethylaminophenyl                                                                          COOCH.sub.3                                                  phenyl           SO.sub.2 CH.sub.3                                            phenyl           SO.sub.2 C.sub.2 H.sub.5                                     2-thienyl        SO.sub.2 C.sub.2 H.sub.5                                     methyl           SO.sub.2 C.sub.2 H.sub.5                                     n-butyl          SO.sub.2 -n-C.sub.6 H.sub.13                                 dodecyl          SO.sub.2 C.sub.6 H.sub.5                                     cyclobutyl       SO.sub.2 CH.sub.2 C.sub.6 H.sub.5                            4-hydroxyphenyl  SO.sub.2 CH.sub.2 C.sub.6 H.sub.5                            3-chloro-4-hydroxyphenyl                                                                       SO.sub.2 C.sub.6 H.sub.5                                     2-butenyl        SO.sub.2 (CH.sub.2).sub.5 CH.sub.3                           2-chlorophenyl   SO.sub.2 -[4-(NO.sub.2)C.sub.6 H.sub.4 ]                     4-methoxyphenyl  SO.sub.2 -[4-BrC.sub.6 H.sub.4)                              4-n-hexoxyphenyl SO.sub.2 -(2-C.sub.2 H.sub.5 C.sub.6 H.sub.4)                4-isopropylthiophenyl                                                                          SO.sub.2 -[3-(n-C.sub.4 H.sub.9)C.sub.6 H.sub.4 ]            3,4-dimethoxyphenyl                                                                            SO.sub.2 -[4-(CH.sub.3 O)C.sub.6 H.sub.4 ]                   3-bromophenyl    SO.sub.2 -(3,4-Cl.sub.2 C.sub.6 H.sub.3)                     4-fluorophenyl   SO.sub.2 -[3-CH.sub.3 -4-(CH.sub.3 O)C.sub.6 H.sub.3 ]       2,4-dichlorophenyl                                                                             SO.sub.2 -[2,4-(NO.sub.2).sub.2 C.sub.6 H.sub.3 ]            3-furyl          SO.sub.2 -[2-CH.sub.3 O-5-(NO.sub.2)C.sub.6 H.sub.3 ]        5-ethyl-2-thienyl                                                                              SO.sub.2 -[3-FC.sub.6 H.sub.4)                               1,4-cyclohexadienyl                                                                            SO.sub.2 C.sub.2 H.sub.5                                     phenyl           phthalidyl                                                   2-thienyl        phthalidyl                                                   1,4-cyclohexadienyl                                                                            phthalidyl                                                   4-hydroxyphenyl  phthalidyl                                                   3-chloro-4-hydroxyphenyl                                                                       phthalidyl                                                   methyl           acetoxymethyl                                                propyl           propionoxymethyl                                             phenyl           isobutyryloxymethyl                                          4-hydroxyphenyl  acetoxymethyl                                                3-chloro-4-hydroxyphenyl                                                                       1-(acetoxy)ethyl                                             2-thienyl        n-hexanoyloxymethyl                                          3-thienyl        1-(n-hexanoyloxy)ethyl                                       1,4-cyclohexadienyl                                                                            pivaloyloxymethyl                                            3-pyridyl        1-(acetoxy)ethyl                                             cyclohexyl       1-(butyrloxy)ethyl                                           2-cyclohexenyl   1-(propionyloxy)ethyl                                        2-furyl          n-pentyloxymethyl                                            2-isothiazolyl   pivaloyloxymethyl                                            4-methoxyphenyl  acetoxymethyl                                                3-fluorophenyl   1-(pivaloyloxy)ethyl                                         4-tolyl          pivaloyloxymethyl                                            5-ethyl-2-thienyl                                                                              pivaloyloxymethyl                                            ______________________________________                                    

EXAMPLE CXCI

Reaction of the appropriate 6-acylamino-2,2-dimethyl-3-(1[2]-substitutedtetrazol-5-yl)penam compound, chosen from those in Examples CLXXXI andCXC with sodium N-(2-ethoxycarbonyl-1-methylvinyl)-2-aminoacetate,according to the procedure of Example CLXXIX produces the followingcompounds:

6-(2-[2-aminoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(1[4-methoxybenzyl]tetrazol-5-yl)penam,

6-(2-[2-aminoacetamido]-2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(1-[methoxycarbonyl]tetrazol-5-yl)penam,

6-(2-[2-aminoacetamido]-2-[3-chloro-4-hydroxy]acetamido)-2,2-dimethyl-3-(1-[ethoxycarbonyl]tetrazol-5-yl)penam,

6-(2-[2-aminoacetamido]-2-[2-thienyl]acetamido)-2,2-dimethyl-3-(1-[ethylsulfonyl]tetrazol-5-yl)penam,

6-(2-[2-aminoacetamido]-n-valeramido)-2,2-dimethyl-3-(1-[n-hexylsulfonyl]tetrazol-5-yl)penam,

6-(2-[2-aminoacetamido]propionamido)-2,2-dimethyl-3-(1-[acetoxymethyl]tetrazol-5-yl)penam,

6-(2-[2-aminoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(1-[isobutyryloxymethyl]tetrazol-5-yl)penam,

6-(2-[2-aminoacetamido]-2-[3-chloro-4-hydroxyphenyl]-acetamido)-2,2-dimethyl-3-(1-[1-(acetoxy)ethyl]tetrazol-5-yl)penam,

6-(2-[2-aminoacetamido]-2-[2-furyl]acetamido)-2,2-dimethyl-3-(1-[n-pentyloxymethyl]tetrazol-5-yl)penam,

6-(2-[2-aminoacetamido]-2-[2-cyclohexyl]acetamido)-2,2-dimethyl-3-(1-[1-(propionyloxy)ethyl]tetrazol-5-yl)penam,

6-(2-[2-aminoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5-yl)penam,

6-(2-[2-aminoacetamido]-2-[2-thienyl]acetamido)-2,2-dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5-yl)penamand

6-(2-[2-aminoacetamido]-2-[3-chloro-4-hydroxyphenyl]-acetamido)-2,2-dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5-yl)penam,

respectively.

EXAMPLE CXCII 6-(2-Phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

A mixture of 100 mg. (1 mmole) of potassium bicarbonate and 2.3 g. of10% palladium-on-carbon, in a mixture of 12 ml. of methanol and 3 ml. ofwater, is stirred under an atmosphere of hydrogen until hydrogen uptakeceases. A solution of 464 mg. of6-(2-phenoxyacetamido)-2,2-dimethyl-3-(1-benzyltetrazol-5-yl)penam in 10ml. of ethyl acetate is then added, and stirring under an atmosphere ofhydrogen is continued for an additional 5 hours. At this point thereaction mixture is filtered, and the residue is washed with aqueousmethanol. The washings and the filtrate are combined and evaporated invacuo. To this latter residue is added chloroform and water and the pHis adjusted to 8.0. The chloroform is removed and discarded, and freshchloroform is added to the aqueous phase. The pH is lowered to 2.5 andthe chloroform layer is separated. The dried chloroform is evaporated invacuo, leaving 190 mg. (51% yield) of6-(2-phenoxyacetamido)-2,2-dimethyl-3 -(5-tetrazolyl)penam.

EXAMPLE CXCIII

The procedure of Example CXCII is repeated, except that the startingmaterial is:

6-(2-phenoxyacetamido)-2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-5-yl)penam,

6-(2-phenoxyacetamido)-2,2-dimethyl-3-(1-[4-hydroxybenzyl]tetrazol-5-yl)penam,

6-(2-[4-methoxyphenoxy]acetamido)-2,2-dimethyl-3-(1-[4-fluorobenzyl]tetrazol-5-yl)penam,

6-benzamido-2,2-dimethyl-3-[1-(3-tolylmethyl)tetrazol-5-yl]penam,

6-isobutyramido-2,2-dimethyl-3-(1-[4-phenylbenzyl]tetrazol-5-yl)penam,

6-(2-amino-2-phenylacetamido)-2,2-dimethyl-3-(1-benzyltetrazol-5-yl)penam,

6-(2-naphthamido)-2,2-dimethyl-3-(1-[3-chloro-4-hydroxybenzyl]tetrazol-5-yl)penamand

6-(1-aminocyclohexanecarboxamido)-2,2-dimethyl-3-(1-benzyltetrazol-5-yl)penam

respectively. This affords:

6-(2-phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-[4-methoxyphenoxy]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-benzamido-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(isobutyramido-2,2-dimethyl-3-(5-tetrazolyl)penam,

6-(2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,,

6-(2-naphthamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and

6-(1-aminocyclohexanecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,

respectively.

EXAMPLE CXCIV 6-(2-Phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred suspension of 2.4 g of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 50 ml of chloroform isadded 2.8 ml of triethylamine. Stirring is continued for a further 15minutes, and then the solution thus obtained, is cooled to 0° C. To thissolution is then 1.08 g of trimethylsilyl chloride. The cooling bath isremoved, and the reaction mixture is stirred for a further 1 hour atambient temperature, to give a chloroform solution of themono-trimethylsilyl derivative of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam. This latter solution is thenrecooled to 0° C., and 1.56 g of phenylacetyl chloride is addeddropwise, with stirring. The cooling bath is removed, and the mixture isstirred for 1 hour at ambient temperature. The chloroform is then washedwith water, dried using anhydrous sodium sulfate, and concentrated todryness in vacuo. This affords crude6-(2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam.

EXAMPLE CXCV

When the procedure of Example CXCIV is repeated, except that thetrimethylsilyl chloride used therein is replaced by an equimolar amountof triethylsilyl chloride and tri-n-butylsilyl chloride, respectively,the product in each case is6-(2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. Theintermediate products in these experiments are the mono-triethylsilyland the mono-tri-n-butylsilyl derivative of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, respectively.

EXAMPLE CXCVI 6-(2-Phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred suspension of 2.4 g of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 50 ml of chloroform isadded 4.2 ml of triethylamine. Stirring is continued for a further 15minutes, and then the solution thus obtained is cooled to 0° C. To thissolution is then added 2.16 g of trimethylsilyl chloride. The coolingbath is removed, and then the reaction mixture is stirred at ambienttemperature for 1 hour and then it is refluxed for 1 hour. It is thencooled to ambient temperature giving a chloroform solution of thebis-trimethylsilyl derivative of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam. This latter solution is thencooled to 0° C., and 1.72 g of phenoxyacetyl chloride is added dropwisewith stirring. The cooling bath is removed, and the mixture is stirredfor 1 hour at ambient temperature. The chloroform is then washed withwater, dried using anhydrous sodium sulfate, and then evaporated todryness in vacuo. This affords crude6-(phenoxyacetamido)-2,2-dimethyl-3-(5 -tetrazolyl)penam.

EXAMPLE CXCVII

When the procedure of Example CXCVI is repeated, except that thetrimethylsilyl chloride used therein is replaced by an equimolar amountof triethylsilyl chloride and triisopropylsilyl chloride, respectively,the product in each case is6-(2-phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. Theintermediate products in these experiments are the bis-triethylsilyl andthe bis-triisopropyl derivative of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, respectively.

EXAMPLE CXCVIII6-Amino-2,2-dimethyl-3-(1[2]-triphenylmethyltetrazol-5-yl)penam

To a stirred slurry of 240 mg. of6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 1.5 ml. of dry,ethanol-free chloroform, is added 0.36 ml. of triethylamine. The mixtureis stirred until a cloudy isolution is obtained, and then ca. 200 mg. ofanhydrous sodium sulfate is added. Stirring is continued for a further15 minutes and then the mixture is filtered. To the filtrate is added278.5 mg. of triphenylmethyl chloride, and the reaction mixture isstored at ambient temperature for 4.5 hours. At this point, the solventis removed by evaporation in vacuo, leaving the crude title product as amixture of isomers as indicated. The crude product is re-dissolved in asmall volume of chloroform and then adsorbed on a small column of silicagel. The column is eluted with chloroform and the first 20 ml. of eluateand collected and evaporated to dryness in vacuo. A small volume ofether is added to the residue, and the mixture is again evaporated todryness in vacuo. The latter residue is washed with ether, to give 357.4mg. (77% yield) of a white solid. The NMR spectrum (CDCl₃) showsabsorptions at 7.15 ppm (broad singlet), 5.70 ppm (doublet), 5.35(singlet), 4.55 (doublet), 1.60 (singlet) and 1.10 (singlet).

EXAMPLE CIC

Reaction of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam with asubstituted triphenylmethyl chloride of formula (R⁵)"-Cl, according tothe procedure of Example CXCVIII affords in each ease a mixture of thecorresponding 6-amino-2,2-dimethyl-3-(1-[substitutedtriphenylmethyl]tetrazol-5-yl)penam and6-amino-2,2-dimethyl-3-(2-[substitutedtriphenylmethyl]tetrazol-5-yl)penam compounds. In this way, thefollowing mixtures are produced:

    ______________________________________                                         ##STR60##                                                                       (R.sup.5)"                                                                 ______________________________________                                        diphenyl(2-fluorophenyl)methyl                                                diphenyl(3-chlorophenyl)methyl                                                diphenyl(4-bromophenyl)methyl                                                 diphenyl(2-ethylphenyl)methyl                                                 diphenyl(4-n-propylphenyl)methyl                                              diphenyl(3-sec-butylphenyl)methyl                                             diphenyl(4-ethoxyphenyl)methyl                                                diphenylbiphenylylmethyl                                                      phenyldi(3-tolyl)methyl                                                       phenyldi(3-chlorophenyl)methyl                                                phenyl(4-chlorophenyl((4-methoxyphenyl)methyl                                 phenyldi(biphenylyl)methyl                                                    tri(4-tolyl)methyl                                                            (4-isopropylphenyl)di(3-methoxyphenyl)methyl                                  ______________________________________                                    

The mixtures are separated into the two isomers by chromatography.

EXAMPLE CC6-(2-Phenoxyacetamido)-2,2-dimethyl-3-(1[2]-triphenylmethyltetrazol-5-yl)penam

To a stirred solution of 932 mg. of6-amino-2,2-dimethyl-3-(1[2]-triphenylmethyltetrazol-5-yl)penam, and0.30 ml. of triethylamine, in 20 ml. of methylene chloride, at 0° C., isadded dropwise, 341 mg. of phenoxyacetyl chloride dissolved in 5 ml. ofmethylene chloride. Stirring is continued at 0° C. for 15 minutes, andthen at 25° C. for one hour. The solvent is removed by evaporation invacuo, and the residue is partitioned between ethyl acetate and water atpH 7.0. The ethyl acetate layer is removed, washed with water, driedusing anhydrous sodium sulfate, and then the solvent is removed byevaporation in vacuo. This affords the title compound as a mixture ofisomers as indicated.

In like manner, acylation of6-amino-2,2-dimethyl-3-(1-triphenylmethyltetrazol-5-yl)penam withphenoxyacetyl chloride provides6-(2-phenoxyacetamido)-2,2-dimethyl-3-(1-triphenylmethyltetrazol-5-yl)penam;and acylation of6-amino-2,2-dimethyl-3-(2-triphenylmethyltetrazol-5-yl)penam withphenoxyacetyl chloride provides6-(2-phenoxyacetamido)-2,2-dimethyl-3-(2-triphenylmethyltetrazol-5-yl)penam.

EXAMPLE CCI

Acylation of the 6-amino-2,2-dimethyl-3(1-[substitutedtriphenylmethyl]tetrazol-5-yl)penam and6-amino-2,2-dimethyl-3-(2-[substitutedtriphenylmethyl]tetrazol-5-yl)penam mixtures of Example CIC withphenoxyacetyl chloride, according to the procedure of Example CC,provides, in each case, mixtures of the corresponding6-(2-phenoxyacetamido)-2,2-dimethyl-3-(1-[substitutedtriphenylmethyl]tetrazol-5-yl)penam and6-(2-phenoxyacetamido)-2,2-dimethyl-3-(2-[substitutedtriphenylmethyl]tetrazol-5-yl)penam compounds. In this way, thefollowing mixtures are produced.

    ______________________________________                                         ##STR61##                                                                      (R.sup.5)"                                                                  ______________________________________                                        diphenyl(2-fluorophenyl)methyl                                                diphenyl(3-chlorophenyl)methyl                                                diphenyl(4-bromophenyl)methyl                                                 diphenyl(2-ethylphenyl)methyl                                                 diphenyl(4-n-prophenyl)methyl                                                 diphenyl(3-sec-butylphenyl)methyl                                             diphenyl(4-ethoxyphenyl)menthyl                                               diphenylbiphenylylmethyl                                                      phenyldi(3-tolyl)methyl                                                       phenyldi(3-chlorphenyl)methyl                                                 phenyl(4-chlorophenyl)(4-methoxyphenyl)methyl                                 phenyldi(biphenylyl)methyl                                                    tri(4-tolyl)methyl                                                            (4-isopropylphenyl)di(3-methoxyphenyl)methyl                                  ______________________________________                                    

EXAMPLE CCII 6-(2-Phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

To a stirred solution of 1.17 g. of6-(2-phenoxyacetamido)-2,2-dimethyl-3-(1[2]-triphenylmethyltetrazol-5-yl)penamin 20 ml. of acetone is added 1.0 ml. of water followed by 50 mg. ofp-toluenesulfonic acid monohydrate. The mixture is stirred at ambienttemperature for one hour, and then the solvent is removed by evaporationin vacuo. To the residue is added 50 ml. of water and 50 ml. of ethylacetate. The pH is adjusted to 7.0, the layers are separated, and theethyl acetate is discarded. Fresh ethyl acetate is added to theremaining aqueous phase, and the pH is adjusted to 2.0. The ethylacetate layer is removed, washed with water, and dried using anhydroussodium sulfate. Evaporation of the solvent in vacuo leaves the crudetitle product.

EXAMPLE CCIII

When each of the 6-(2-phenoxyacetamido)-2,2-dimethyl-3-(1-[substitutedtriphenylmethyl]tetrazol-5-yl)penam and6-(2-phenoxyacetamido)-2,2-dimethyl-3-(2-[substitutedtriphenylmethyl]tetrazol-5-yl)penam mixtures, selected from those inExample CCI, are subjected to the reaction conditions of Example CCII,the product in each case is2-(phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam.

EXAMPLE CCIV6-(D-2-Amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamhydrochloride

A slurry of 50 mg. of6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 2ml. of de-ionized water is stirred for 5 minutes at ambient temperature.The pH is then adjusted to 2.45 using dilute hydrochloric acid, and thesolution thus obtained is immediately lyophilized. This affords 52 mg.Of 6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamhydrochloride as a fluffy white solid.

EXAMPLE CCV6-(D-2-Amino-2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam,Potassium Salt

To a stirred solution of 1.94 g.(D-2-amino-2-[4-hydroxyphenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamin 100 ml. of methanol, cooled to -30° C., is added dropwise 5 ml. of a1.0 N solution of potassium hydroxide in methanol. The mixture isallowed to warm to 0° C., and then it is added dropwise with stirring to700 ml. of ether. The solid which precipitates is removed by filtrationand dried under high vacuum. This affords 1.65 g. (76% yield) of thetitle potassium salt, m.p. 185° C. (dec.).

When the above procedure is repeated, except that the potassiumhydroxide used therein is replaced by an equimolar amount of sodiumhydroxide, the product is the sodium salt of6-(D-2-amino-2-(4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam.

EXAMPLE CCVI6-(D-2-Amino-2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamCalcium Salt

To a stirred solution of 2.0 g. of6-(D-2-amino-2-[4-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamin 20 ml. of dimethylformamide is added a turbid solution of 0.19 g. ofcalcium hydroxide in 100 ml. of dimethylforamamide, over 5 minutes. Themixture is heated at 35°-40° C. for 1 hour, and then an additional 30ml. of dimethylformamide is added. Heating at 35°-40° C. is continuedfor a further 30 minutes, and then the cooled solution is added dropwiseto 700 ml. of ether. An oil precipitates. The solvent is decanted offand to the residue is added 100 ml. of ethanol, followed by 400 ml. ofether. The oil slowly solidifies and then it is recovered by filtrationand dried under high vacuum. This affords 1.4 g. (67% yield) of thetitle calcium salt.

EXAMPLE CCX

In vitro antibacterial activities for a number of the compounds of thisinvention are presented below.

In Table II, the minimum inhibitory concentrations (MIC's) of compoundsof formula I, wherein R² is hydrogen, against a strain of Streptococcuspyogenes, are reported; and in Table III, minimum inhibitoryconcentrations of compounds of formula I, wherein R² is hydrogen,against a strain of Staphylococcus aureus, are presented. Because of thetautomeric nature of such tetrazole derivatives, referred tohereinbefore, each of the preparations tested also contains some of thecorresponding compound of formula II, wherein R³ is hydrogen.

                                      TABLE II                                    __________________________________________________________________________                                   MIC (μg/ml) vs. Strep.                        R.sup.1                      pyogenes                                       __________________________________________________________________________    2-phenylacetyl                 <0.1                                           3-(o-chlorophenyl)-5-methyl-4-isoxazolecarbonyl                                                              <0.1                                           2-azido-2-phenylacetyl         <0.1                                           2-cyanoacetyl                  0.1                                            2-(1-tetrazolyl)acetyl         <0.39                                          2-phenoxyacetyl                <0.1                                           phenoxycarbonyl                <0.1                                           benzyloxycarbonyl              <0.1                                           ethoxycarbonyl                 <0.1                                           acetyl                         <0.1                                           2-bromoacetyl                  <0.1                                           2-(4-pyridylthio)acetyl        <0.1                                           2-(N,N'-diethylamidinothio)acetyl                                                                            <0.1                                           hydrogen                       <0.1                                           3-(carbamoyl)acryloyl          <0.1                                           2,6-dimethoxybenzoyl           0.2                                            D-2-amino-2-phenylacetyl       <0.1                                           D-2-amino-2-(m-hydroxyphenyl)acetyl                                                                          <0.1                                           DL-2-amino-2-(3,4-dihydroxyphenyl)acetyl                                                                     <0.1                                           L-2-amino-2-(p-hydroxyphenyl)acetyl                                                                          <0.1                                           D-2-amino-2-(2-thienyl)acetyl  0.1                                            DL-2-amino-2-(p-[N,N-dimethylamino]phenyl)acetyl                                                             0.39                                           D-2-amino-2-(3-chloro-4-hydroxyphenyl)acetyl                                                                 0.1                                            DL-2-amino-2-(p-chlorophenyl)acetyl                                                                          <0.1                                           DL-2-amino-2-(m-chlorophenyl)acetyl                                                                          0.78                                           DL-2-amino-2-(2-bromo-5-hydroxyphenyl)acetyl                                                                 <0.1                                           D-2-amino-2-(m-fluorophenyl)acetyl                                                                           <0.1                                           D-2-amino-3-methylbutyryl      0.2                                            D-2-amino-3-phenylpropionyl    0.39                                           D-2-amino-2-(p-hydroxyphenyl)acetyl                                                                          <0.1                                           1-aminocyclohexylcarbonyl      25                                             D-2-amino-2-(1,4-cyclohexadienyl)acetyl                                                                      <0.1                                           DL-3-amino-2-phenylpropionyl   12.5                                           2-(o-[aminomethyl]phenyl)acetyl                                                                              <0.1                                           2-(o-[2-aminoethoxy]phenyl)acetyl                                                                            <0.1                                           L-2-amino-3-(p-hydroxyphenyl)propionyl                                                                       0.2                                            2-(benzamido)acetyl            0.1                                            2-(2-bromoacetamido)-2-phenylacetyl                                                                          <0.1                                           2-(2-[Δ.sup.1 -imidazolin-2-ylthio]acetamido)-2-phenylacetyl                                           <0.1                                           D-2-(p-methoxybenzenesulfonamido)-2-phenylacetyl                                                             0.2                                            D-2-(naphthalenesulfonamido)-2-phenylacetyl                                                                  0.2                                            D-2-(2-thiophenesulfonamido)-2-phenylacetyl                                                                  0.39                                           D-2-(ethanesulfonamido)-2-phenylacetyl                                                                       0.39                                           D-2-(2-[methanesulfonamido]acetamido)-2-phenylacetyl                                                         <0.1                                           D-2-(2-[benzenesulfonamido]acetamido)-2-phenylacetyl                                                         <0.1                                           D-2-(2-[α-toluenesulfonamido]acetamido)-2-phenylacetyl                                                 <0.1                                           D-2-(benzenesulfonamido)-2-(p-hydroxyphenyl)acetyl                                                           <0.1                                           D-2-(propanesulfonamido)-2-(p-hydroxyphenyl)acetyl                                                           0.1                                            D-2-(2-[benzamido]acetamido)-2-phenylacetyl                                                                  <0.1                                           D-2-(2-[acetamido]acetamido)-2-phenylacetyl                                                                  <0.1                                           D-2-(2-[propionamido]acetamido)-2-phenylacetyl                                                               <0.1                                           D-2-(2-[p-chlorobenzamido]acetamido)-2-phenylacetyl                                                          0.1                                            D-2-(2-[p-nitrobenzamido]acetamido)-2-phenylacetyl                                                           <0.1                                           D-2-(2-[p-methoxybenzamido]acetamido)-2-phenylacetyl                                                         0.1                                            D-2-(2-[butyramido]acetamido)-2-phenylacetyl                                                                 <0.1                                           D-2-(2-[ethoxycarbonylamino]acetamido)-2-phenylacetyl                                                        <0.1                                           D-2-(2-[benzyloxycarbonylamino]acetamido)-2-phenylacetyl                                                     0.39                                           D-2-(3-phenylureido)-2-(p-hydroxyphenyl)acetyl                                                               <0.1                                           D-2-(3-[p-methoxyphenyl]ureido)-2-phenylacetyl                                                               <0.1                                           D-2-(3-[p-chlorophenyl]ureido)-2-phenylacetyl                                                                <0.1                                           D-2-(3-[p-tolyl]ureido)-2-phenylacetyl                                                                       <0.1                                           D-2-(3-phenylureido)-2-phenylacetyl                                                                          <0.1                                           D-2-(3-methylureido)-2-phenylacetyl                                                                          50                                             D-2-(3-[p-methoxyphenyl]ureido)-2-(p-hydroxyphenyl)acetyl                                                    <0.1                                           D-2-(3-[p-chlorophenyl]ureido)-2-(p-hydroxyphenyl)acetyl                                                     <0.1                                           D-2-(2-aminoacetamido)-2-phenylacetyl                                                                        <0.1                                           D-2-(2-aminoacetamido)-2-(p-hydroxyphenyl)acetyl                                                             <0.1                                           D-2-(2-[benzamidino]acetamido)-2-phenylacetyl                                                                <0.1                                           D-2-(2-[4-pyridinecarboxamidino]acetamido)-2-phenylacetyl                                                    <0.1                                           D-2-(2-[4-pyridine-N-oxide-carboxamidino]acetamido)-2-                        phenylacetyl                   <0.1                                           D-2-(2-[2-(p-chlorophenyl)acetamidino]acetamido)-2-                           phenylacetyl                   0.2                                            D-2-(2-[p-nitrobenzamidino]acetamido)-2-phenylacetyl                                                         <0.1                                           D-2-(2-[m-sulfamoylbenzamidino]acetamido)-2-phenylacetyl                                                     <0.1                                           D-2-(2-[m-cyanobenzamidino]acetamido)-2-phenylacetyl                                                         6.25                                           D-2-(2-[2-benzimidizolecarboxamidino]acetamido)-2-                            phenylacetyl                   <0.1                                           D-2-(2-[2-pyridmidinecarboxamidino]acetamido)-2-phenyl-                       acetyl                         0.78                                           D-2-(2-[3-cyano-5-iodobenzamidino]acetamido)-2-phenyl-                        acetyl                         <0.1                                           2-(3,5-dimethylbenzamidino)acetyl                                                                            0.39                                           2-(4-pyridinecarboxamidino)acetyl                                                                            <0.1                                           2-(acetamidino)acetyl          <0.1                                           2-(2-thiophenecarboxamidino)acetyl                                                                           <0.1                                           2-(4-pyridinecarboxamidino)-3-phenylpropionyl                                                                0.2                                            D-2-(2-[4-pyridinecarboxamidino]acetamido)-2-(p-hydroxy-                      phenyl)acetyl                  <0.1                                           D-2-(2-[3-ethylureido]acetamido)-2-phenylacetyl                                                              <0.1                                           D-2-(2-[3-phenylureido]acetamido)-2-phenylacetyl                                                             <0.1                                           D-2-(2-[3-methylureido]acetamido)-2-phenylacetyl                                                             <0.1                                           D-2-(3-guanylureido)-2-phenylacetyl                                                                          <0.1                                           D-2-ureido-2-phenylacetyl      0.1                                            2-sulfamoyl-2-phenylacetyl     <0.1                                           D-2-(p-guanidinobenzamido)-2-phenylacetyl                                                                    1.56                                           D-2-(2-[guanidino]acetamido)-2-phenylacetyl                                                                  <0.1                                           D-2-(2-[p-guanidinophenyl]acetamido)-2-phenylacetyl                                                          1.56                                           D-2-(3-[guanyl]propionamido)-2-phenylacetyl                                                                  <0.1                                           D-2-(2-[N-methylguanidino]acetamido)-2-phenylacetyl                                                          <0.1                                           D-2-(2-[3-guanyl)ureido]acetamido)-2-phenylacetyl                                                            3.12                                           D-2-(3-[2-furoyl]ureido)-2-phenylacetyl                                                                      <0.1                                           2-(3-acetylureido)-2-phenylacetyl                                                                            <0.1                                           2-(3-butyrylureido)-2-phenylacetyl                                                                           <0.1                                           2-(3-[chloroacetyl]ureido)-2-phenylacetyl                                                                    0.2                                            2-(3-[3-pyridylcarbonyl]-ureido)-2-phenylacetyl                                                              0.1                                            2-(3-benzoylureido)-2-phenylacetyl                                                                           <0.1                                           2-(3-[3,5-dibromobenzoyl]-ureido)-2-phenylacetyl                                                             <0.1                                           2-(3-[4-pyridylcarbonyl]-ureido)-2-phenylacetyl                                                              0.2                                            2-(3-propionylureido)-2-phenylacetyl                                                                         <0.1                                           2-(3-[cyclopropylcarbonyl]-ureido)-2-phenylacetyl                                                            <0.1                                           2-(3-[1-adamantylcarbonyl]-ureido)-2-phenylacetyl                                                            <0.1                                           2-(3-benzoylthioureido)-2-phenylacetyl                                                                       1.56                                           N-acetylcarbomoyl              1.56                                           N-(2-furoyl)carbamoyl          1.56                                           N-(p-toluenesulfonyl)carbonyl  1.56                                           2-carboxy-2-phenylacetyl       0.002                                          2-carboxy-2-(2-thienyl)acetyl  0.1                                            2-carboxy-2-(3-thienyl)acetyl  0.1                                            2-sulfo-2-phenylacetyl         200                                            2-(5-indanyloxycarbonyl)-2-phenylacetyl                                                                      <0.1                                           D-2-sulfoamino-2-phenylacetyl  12.5                                           phenylpyruvoyl                 <0.1                                           phenylglyoxyloyl               <0.1                                           D-2-(benzoylformamido)-2-phenylacetyl                                                                        25                                             D-2-(acetylformamido)-2-phenylacetyl                                                                         50                                             D-2-(ethoxycarbonylformamido)-2-phenylacetyl                                                                 <0.1                                           D-2-(phenoxycarbonylformamido)-2-phenylacetyl                                                                25                                             D-2-(ethoxycarbonylamino)-2-phenylacetyl                                                                     6.25                                           D-2-(benzyloxycarbonylamino)-2-phenylacetyl                                                                  <0.1                                           D-2-(2-carboxy-3-[2-thienyl]acrylamido)-2-phenylacetyl                                                       <0.1                                           D-2-(2-carboxy-3-[p-chlorophenyl]acrylamido)-2-phenyl-                        acetyl                         <0.1                                           D-2-allophanamido-2-phenylacetyl                                                                             <0.1                                           3-aminomethyl-2-phenylisocrotonoyl                                                                           12.5                                           D-2-(dimethylaminomethyleneamino)-2-phenylacetyl                                                             <0.1                                           D-2-(dimethylaminomethyleneamine)-2-(p-hydroxyphenyl)acetyl                                                  <0.1                                           2-(3-[2-(p-chlorophenyl)acetimidoyl]ureido)acetyl                                                            100                                            2-(3-[benzimidoyl]ureido)-acetyl                                                                             <0.1                                           2-(3-[p-methoxybenzimidoyl]-uredio)acetyl                                                                    0.1                                            2-(2-[3-(2-[p-chlorophenyl]-acetimidoyl)ureido]acetamido)-                    2-phenylacetyl                 <0.1                                           2-(2-[3-(benzimidoyl)ureido]-acetamido)-2-phenylacetyl                                                       0.78                                           2-(2-[3-(p-methoxybenzimidoyl)ureido]acetamido-2-phenylacetyl                                                1.56                                           3-phenylcarbamoyl              <0.1                                           3-ethylcarbamoyl               <0.1                                           D-2-(2-phenylacetamido)-2-phenylacetyl                                                                       <0.1                                           D-2-(benzamido)-2-phenylacetyl <0.1                                           D-2-(butyramido)-2-phenylacetyl                                                                              0.39                                           D-2-(2-furancarboxamido)-2-phenylacetyl                                                                      0.1                                            D-2-(2-thiophenecarboxamido)-2-phenylacetyl                                                                  <0.1                                           D-2-(2-[2-thienyl]acetamido)-2-phenylacetyl                                                                  0.1                                            D-2-(3-pyridinecarboxamido)-2-phenylacetyl                                                                   <0.1                                           D-2-(2-pyrrolecarboxamido)-2-phenylacetyl                                                                    <0.1                                           D-2-(2-[2-quinoxalinecarboxamidino]acetamido)-2-phenylacetyl                                                 0.1                                            D-2-(2-[m-carbamoylbenzamidino]acetamido)-2-phenylacetyl                                                     <0.1                                           D-2-(carboxymethyl)acetamido-2-phenyl-                                                                       0.2                                            acetyl                                                                        D-2-(4-carboxy-2,3-epoxypropionamido)-                                                                       0.2                                            2-phenylacetyl                                                                2-(4-aminomethylphenyl)acetyl  <0.1                                           2-(2-[carboxymethyl]phenyl)acetyl                                                                            0.2                                            2-amino-2-(4-aminophenyl)acetyl                                                                              0.039                                          D-2-amino-2-(3-aminophenyl)acetyl                                             D-2-acetyl-2-phenylacetyl      0.004                                          2-(4-[2-azidoethoxy]phenyl)acetyl                                                                            <0.1                                           D-2-(3-[2-(guanylthio)acetyl]ureido)-2-                                                                      0.004                                          phenylacetyl                                                                  D-2-(3-phenylthioureido)-2-phenylacetyl                                                                      <0.1                                           D-2-phthalimido-2-phenylacetyl 0.004                                          D-2-(4-aminobenzamido)-2-phenylacetyl                                                                        <0.1                                           D-2-(2-[4-aminophenyl]acetamido)-2-                                                                          <0.1                                           phenylacetyl                                                                  D-2-(2-phenoxyacetamido)-2-(4-hydroxy-                                                                       0.2                                            phenyl)acetyl                                                                 D-2-(3-[2-(N,N'-diethylguanylthio)acetyl]-                                                                   0.004                                          ureido)-2-phenylacetyl                                                        2-ethoxy-1-naphthoyl           <0.1                                           DL-2-amino-2-(m-nitrophenyl)acetyl                                                                           0.004                                          DL-2-amino-2-(p-sulfamoylphenyl)acetyl                                                                       <0.1                                           D-2-amino-2-(p-fluorophenyl)acetyl                                                                           3.12                                           D-2-amino-2-(2-furyl)acetyl    0.39                                           D-2-amino-2-(2-tetrahydrofuryl)acetyl                                                                        <0.1                                           DL-2-amino-2-(3-pyridyl)acetyl <0.1                                           D-2-amino-(4-aminophenyl)acetyl                                                                              0.39                                           D-2-amino-(3-aminophenyl)acetyl                                                                              <0.01                                          2-(2-[aminomethyl]phenylthio)acetyl                                                                          1.56                                           2-(3-[2-aminoethoxy]phenyl)acetyl                                                                            <0.1                                           2-(4-[2-aminoethoxy]phenyl)acetyl                                                                            <0.1                                           D-2-(2-chloroacetamido)-2-phenylacetyl                                                                       <0.1                                           D-2-(2-chloroacetamido)-2-(2-furyl)acetyl                                                                    <0.1                                           D-2-([N,N'-dimethylamidinothio]acetamido-                                                                    0.004                                          2-phenylacetyl                                                                D-2-(2-[pentamethyleneamidinothio]-                                                                          <0.1                                           acetamido)-2-phenylacetyl                                                     D-2-(2-[2-benzimidazoylthio]acetamido)-2-                                                                    <0.1                                           phenylacetyl                                                                  D-2-(2-[N,N'-diethylamidinothio]acetamido)-                                                                  0.004                                          2-phenylacetyl                                                                D-2-(2-[N,N'-dibutylamidinothio]acetamido)-                                                                  0.004                                          2-phenylacetyl                                                                D-2-(2-[4-oxo-Δ.sup.2 -imidazolin-2-ylthio]-                                                           0.1                                            acetamido)-2-phenylacetyl                                                     D-2-(2-[amidinothio]acetamido)-2-                                                                            0.004                                          phenylacetyl                                                                  D-2-(2-[2-imidazolythio]acetamido)-2-                                                                        0.2                                            phenylacetyl                                                                  D-2-(3-aminopropionamido)-2-phenylacetyl                                                                     <0.1                                           2-(phenylthio)acetyl           0.78                                           D-2-(2-[phenylthio]acetamido)-2-phenyl-                                                                      <0.1                                           acetyl                                                                        2-(ethylthio)acetyl            <0.1                                           D-2-(2-[ethylthio]acetamido)-2-phenyl-                                                                       <0.1                                           acetyl                                                                        3-(methoxycarbonyl)butyryl     6.25                                           D-2-(3-[methoxycarbonyl]butyramido)-2-                                                                       6.25                                           phenylacetyl                                                                  2-(ethoxycarbonyl)acetyl       0.39                                           D-2-(2-[ethoxycarbonyl]acetamido)-2-                                                                         <0.1                                           phenylacetyl                                                                  2-(benzylthio)acetyl           0.2                                            D-2-(2-[benzylthio]acetamido)-2-phenyl-                                                                      0.78                                           acetyl                                                                        D-2-(3-benzamidopropionamido)-2-phenyl-                                                                      <0.1                                           acetyl                                                                        D-2-(3-[4-chlorobenzamido]propionamido)-2-                                                                   <0.1                                           phenylacetyl                                                                  D-2-(3-[3-chlorobenzamido]propionamido)-2-                                                                   <0.1                                           phenylacetyl                                                                  D-2-(3-[2-furancarboxamido]propionamido)-                                                                    <0.1                                           2-phenylacetyl                                                                D-2-(3-acetamidopropionamido)-2-phenyl-                                                                      <0.1                                           acetyl                                                                        D-2-(3-benzamidinopropionamido)-2-phenyl-                                                                    3.12                                           acetyl                                                                        D-2-(3-[3,5-dibromobenzamidino]propion-                                                                      <0.1                                           amido)-2-phenylacetyl                                                         D-2-(3-acetamidinopropionamido)-2-phenyl-                                                                    <0.1                                           acetyl                                                                        D-2-(3-[3,4-dichlorobenzamidino]propion-                                                                     0.78                                           amido)-2-phenylacetyl                                                         D-2-(3-[4-chlorophenyl]acetamidinopropion-                                                                   1.56                                           amido)-2-phenylacetyl                                                         D-2-(2-[3-(N-methylguanyl)ureido]acetamido)-                                                                 <0.1                                           2-phenylacetyl                                                                D-2-(2-[ 3-(N-ethylguanyl)ureido]-acetami-                                                                   <0.1                                           do)-2-phenylacetyl                                                            D-2-(2-[3-(N-benzylguanyl)ureido]acet-                                                                       0.1                                            amido)-2-phenylacetyl                                                         D-2-(2-[2-benzthiazolecarboxamidino]-                                         acetamido)-2-phenylacetyl      <0.1                                           D-2-(2-[3,5-disulfamoylbenzamidino]-                                                                         0.004                                          acetamido)-2-phenylacetyl                                                     D-2-(2-[3-sulfamoyl-5-bromobenzamidino]-                                                                     0.0004                                         acetamido)-2-phenylacetyl                                                     D-2-(2-[3-chloro-5-cyanobenzamidino]acet-                                                                    0.004                                          amido)-2-phenylacetyl                                                         D-2-(2-[2-benzoxazolecarboxamidino]acet-                                                                     0.39                                           amido)-2-phenylacetyl                                                         D-2-(2-[3-sulfamoyl-5-chlorobenzamidino]-                                                                    0.004                                          acetamido)-2-phenylacetyl                                                     D-2-(3-[4-pyridinecarboxamidino)propion-                                                                     <0.1                                           amido)-2-phenylacetyl                                                         D-2-(3-pyridine-1-oxide-4-carboxamidino]-                                                                    3.12                                           propionamido)-2-phenylacetyl                                                  D-2-(3-[2-thienylcarboxamidino]propion-                                                                      <0.1                                           amido)-2-phenylacetyl                                                         D-2-(2-[3-(N-p-chlorobenzylgurnyl)ureido]-                                                                   0.39                                           acetamido)-2-phenylacetyl                                                     D-2-(2-[3-(N-[  cyclohexylmethyl]guanyl)-                                                                    0.2                                            ureido]acetamido)-2-phenylacetyl                                              D-2-(2-[3-(N-[4-pyridylmethyl]guanyl)-                                                                       0.004                                          ureido]acetamido)-2-phenylacetyl                                              D-2-(2-[3-(guanyl)ureido]acetamido)-2-                                                                       0.004                                          (4-hydroxyphenyl(acetyl                                                       D-2-(3-[2-phenylacetyl]ureido)-2-                                                                            <0.1                                           phenylacetyl                                                                  D-2-(3-[benzyloxycarbonyl]ureido)-2-                                                                         0.004                                          phenylacetyl                                                                  D-2-(3-[acetyl]thioureido)-2-phenylacetyl                                                                    3.2                                            D-2-(3-[3-methyl-5-isoxazolycarbonyl]-                                                                       <0.1                                           ureido)-2-phenylacetyl                                                        D-2-(2-[4-bromophenyl]acetamido)-2-phenyl-                                                                   0.2                                            acetyl                                                                        D-2-(2-[4-methoxyphenyl]acetamido)-2-phenyl-                                                                 0.1                                            acetyl                                                                        D-2-(4-pyridinecarboxamido)-2-phenylacetyl                                                                   3.12                                           D-2-(2-[4-nitrophenyl]acetamido)-2-phenyl-                                                                   <0.1                                           acetyl                                                                        D-2-(2-[2-furyl]acetamido)-2-phenylacetyl                                                                    <0.1                                           D-2-(4-nitrobenzamido)-2-phenylacetyl                                                                        0.004                                          D-2-(2-phenoxyacetamido)-2-phenylacetyl                                                                      0.004                                          D-2-(2-cyanoacetamido)-2-phenylacetyl                                                                        0.004                                          D-2-(2-azicoacetamido)-2-phenylacetyl                                                                        0.2                                            D-2-(2-[3-(guanyl)ureido]acetamido)-2-(4-                                                                    0.004                                          hydroxyphenyl)acetyl                                                          D-2-(3-[guanyl]ureido)-2-(4-hydroxyphenyl)-                                                                  0.004                                          acetyl                                                                        D-2-(2-[3-benzoylureido]acetamido)-2-phenyl-                                                                 <0.1                                           acetyl                                                                        D-2-(2-[3-methanesulfonylureido]acetamido)-                                                                  0.2                                            2-phenylacetyl                                                                D-2-(3-[3-ethylthioureido]propionamido)-2-                                                                   0.39                                           phenylacetyl                                                                  D-2-(3-[3-phenylthioureido]propionamido)-2-                                                                  1.56                                           phenylacetyl                                                                  D-2-(3-[3-methylureido]propionamido)-2-                                                                      <0.1                                           phenylacetyl                                                                  D-2-(3-[3-phenylureido]propionamido)-2-                                                                      <0.1                                           phenylacetyl                                                                  2-(3-azidomethyl-2-thienyl-    ≦0.1                                    acetyl                                                                        2-(3-aminomethyl-2-thienyl)-   ≦0.1                                    acetyl                                                                        2-(5-azidomethyl-2-thienyl)-   ≦0.1                                    acetyl                                                                        2-(5-aminomethyl-2-thienyl)-   ≦0.1                                    acetyl                                                                        2-(2-azidomethylphenyl)acetyl  ≦0.1                                    __________________________________________________________________________

                                      TABLE III                                   __________________________________________________________________________                                 MIC (μg/ml) vs. Staph.                          R.sup.1                    aureus                                           __________________________________________________________________________    D-2-amino-2-(p-methoxyphenyl)acetyl                                                                        <0.1                                             2-aminoacetyl                200                                              D-2-amino-3-(3-indolyl)propionyl                                                                           6.25                                             D-2-amino-2-(3-thienyl)acetyl                                                                              <0.1                                             2-(2-[4-pyridylthio]acetamido)-2-phenylacetyl                                                              100                                              D-2-(methanesulfonamido)-2-phenylacetyl                                                                    1.56                                             D-2-(propanesulfonamido)-2-phenylacetyl                                                                    0.78                                             D-2-(p-chlorobenzenesulfonamido)-2-phenylacetyl                                                            1.56                                             D-2-(p-nitrobenzenesulfonamido)-2-phenylacetyl                                                             1.56                                             D-2-(α-toluenesulfonamido)-2-phenylacetyl                                                            0.39                                             D-2-(2-[3,5-dibromobenzamidino]acetamido)-2-phenylacetyl                                                   1.56                                             D-2-(2-[acetamidino]acetamido)-2-phenylacetyl                                                              1.56                                             2-(4-pyridinecarboxamidino)-3-methylbutyryl                                                                50                                               D-2-(2-[guanyl]acetamido)-2-phenylacetyl                                                                   12.5                                             D-2-(2-[Δ.sup.1 -imidazolin-2-yl]acetamido)-2-phenylacetyl                                           3.12                                             2-(3-[2-furoyl]thioureido)-2-phenylacetyl                                                                  0.78                                             2-(3-[p-toluenesulfonly]-ureido)-2-phenylacetyl                                                            6.25                                             L-2-hydroxy-2-phenylacetyl   <0.1                                             D-2-hydroxy-2-phenylacetyl   <0.1                                             D-2-(2-[dimethylaminomethyleneamino]acetamido)-2-phenyl-                      acetyl                       6.25                                             D-2-(acetamido)-2-phenylacetyl                                                                             0.78                                             D-2-(2-[2-pyrrolecarboxamidino]acetamido)-2-phenylacetyl                                                   50                                               __________________________________________________________________________

Minimum inhibitory concentrations of other compounds of this inventionare presented in Table IV.

                  TABLE IV                                                        ______________________________________                                                                    MIC                                                                           (μg/ml)                                                                    vs. Strep.                                          Compound                  pyrogenes                                         ______________________________________                                        6-(5-oxo-4-phenyl-1-imidazolidinyl)-2,2-                                      dimethyl-3-(5-tetrazolyl)penam                                                                            6.25                                              6-(5-oxo-4-[p-hydroxyphenyl]imidazolidinyl)-2,-                               2-dimethyl-3-(5-tetrazolyl)penam                                                                          6.25                                              6-(2,2-dimethyl-5-oxo-4-phenyl-1-imidazoli-                                   dinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam                                                                 1.56*                                             6-(2,2-dimethyl-5-oxo-4-[p-hydroxyphenyl]-1-                                  imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)-                                penam                       0.78*                                             6-([hexahydro-1-azepinyl]methayleneamino)-2,2-                                dimethyl-3-(5-tetrazolyl)penam                                                                            50                                                6-([dimethylamino]methyleneamino-2,2-dimethyl-                                3-(5-tetrazolyl)penam       12.5                                              6-(2-phenylacetamido)-2,2-dimethyl-3-(1-[2]-                                  pivaloyloxymethyl-tetrazol-5-yl)penam                                                                     0.2                                               6-(D-2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-                               dimethyl-3-(2-pivaloyloxymethyltetrazol-5-yl)penam                                                        0.39                                              6-(2-[2-aminomethylphenyl]acetamido)-2,2-dimethyl-                            3-(1-[2]pivaloyloxymethyltetrazol-5-yl)penam                                                              <0.1                                              ______________________________________                                         *MIC against Staph. aureus                                               

What is claimed is:
 1. A method of treating bacterial infections in amammal which comprises administering to said mammal an antibacterialeffective amount of a compound having antibacterial activity andselected from the group consisting of ##STR62## and the pharmaceuticallyacceptable salts thereof wherein R¹ is an acyl group of an organiccarboxylic acid or the acyl group of an acyl derivative selected fromthe group consisting of esters, amides and chlorides of organiccarboxylic acids and R² and R³ are each selected from the groupconsisting of hydrogen, alkanoyloxymethyl having from 3 to 8 carbonatoms, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms and3-phthalidyl.
 2. The method according to claim 1, wherein R¹ is##STR63## wherein n is 0 or 1; R⁷ is selected from the group consistingof hydrogen, alkyl having from one to twelve carbon atoms, alkenylhaving from two to twelve carbon atoms, cycloalkyl having from three toseven carbon atoms, cycloalkenyl having from five to eight carbon atoms,cycloheptatrienyl, 1,4-cyclohexadienyl, 1-aminocycloalkyl having fromfour to seven carbon atoms, cyanomethyl, 5-methyl-3-phenyl-4-isoxazolyl,5-methyl-3-(o-chlorophenyl)-4-isoxazolyl,5-methyl-3-(2,6-dichlorophenyl)-4-isoxazolyl,5-methyl-3-(2-chloro-6-fluorophenyl)-4-isoxazolyl, 2-alkoxy-1-naphthylhaving from one to four carbon atoms in said alkoxy, phenyl, phenoxy,phenylthio, pyridylthio, benzyl, sydnonyl, thienyl, furyl, pyridyl,thiazolyl, isothiazolyl, pyrimidinyl, tetrazolyl, triazolyl, imidazolyl,pyrazolyl, substituted phenyl, substituted phenoxy, substitutedphenylthio, substituted pyridylthio, substituted benzyl, substitutedthienyl, substituted furyl, substituted pyridyl, substituted tetrazolyl,substitued thiazolyl, substituted isothiazolyl, substitued pyrimidinyl,subtriazolyl, substitued imidazolyl and substituted pyrazolyl, eachsubstituted moiety being substituted by up to two members selected fromthe group consisting of fluoro, chloro, bromo, hydroxy, hydroxymethyl,amino, N,N-dialkylamino having from one to four carbon atoms in each ofsaid alkyl groups, alkyl having from one to four carbon atoms,aminomethyl, aminoethyl, alkoxy having from one to four carbon atoms,alkylthio having from one to four carbon atoms, 2-aminoethoxy andN-alkylamino having from one to four carbon atoms;and Q is selected fromthe group consisting of hydrogen, alkyl having from one to six carbonatoms, hydroxy, azido, carboxy, sulfo, carbamoyl, phenoxycarbonyl,indanyloxycarbonyl, sulfoamino, aminomethyl, amino and NH--(CO--CH₂--NH)_(m) --CO--Z; wherein Z is selected from the group consisting ofalkyl having from one to six carbon atoms, phenyl, substituted phenyl,furyl, thienyl, pyridyl, pyrrolyl, amino, N-alkylamino having from oneto six carbon atoms, anilino, substituted anilino, guanidino,alkanoylamino having from two to seven carbon atoms, benzamido,substituted benzamido, thiophenecarboxyamido, furancarboxamido,pyridinecarboxamido, aminomethyl, guanidinomethyl,alkanecarboxyamidinomethyl having from three to eight carbon atoms,benzamidinomethyl, (substituted benzamidino)methyl,thiophenecarboxamidinomethyl, furancarboxamidinomethyl,pyridinecarboxamidinomethyl, pyrrolecarboxamidinomethyl and2-benzimidazolecarboxamidinomethyl, each substituted moiety beingsubstituted by up to two members selected from the group consisting offluoro, chloro, bromo, iodo, alkyl having from one to four carbon atomsalkoxy having from one to four carbon atoms, sulfamyl, carbamoyl andcyano; and m is 0 or 1:provided that when R⁷ is 1-aminocycloalkyl, n is0; and provided that when R⁷ is selected from the group consisting ofphenoxy, phenylthio, pyridylthio, substituted phenoxy, substitutedphenylthio and substitued pyridylthio and n is 1, Q is selected from thegroup consisting of hydrogen, alkyl having from one to six carbon atoms,carboxy, sulfo, carbamoyl, phenoxycarbonyl, substituted phenoxycarbonyl,indanyloxycarbonyl and aminomethyl.
 3. The method according to claim 2,wherein R² and R³ are each hydrogen, n is 1, R⁷ is phenyl and Q ishydrogen.
 4. The method according to claim 2, wherein R² and R³ are eachhydrogen, n is 1, R⁷ is phenoxy and Q is hydrogen.
 5. The methodaccording to claim 2, wherein R² and R³ are each hydrogen, n is 1, andR⁷ is selected from the group consisting of phenyl and said substitutedphenyl.
 6. The method according to claim 5, wherein Q is amino.
 7. Themethod according to claim 6, wherein R⁷ is phenyl.
 8. The methodaccording to claim 6, wherein R⁷ is 4-hydroxyphenyl.
 9. The methodaccording to claim 6, wherein R⁷ is 3-chloro-4-hydroxyphenyl.